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Researchers have created, for the first time, a miniature human heart model in the laboratory.

The mini-hearts are complete with all primary heart cell types and a functioning structure of chambers and vascular tissue.

The organoids are small models of the fetal heart with representative functional and structural features. They are, however, not as perfect as a human heart yet. That is something we are working toward.

These mini-hearts constitute incredibly powerful models in which to study all kinds of cardiac disorders with a degree of precision unseen before, says Aitor Aguirre, assistant professor of biomedical engineering at Michigan State Universitys Institute for Quantitative Health Science and Engineering and senior author of the study on the work on the bioRxiv preprint server. In the United States, heart disease is the leading cause of death.

The researchers created the human heart organoids, or hHOs for short,by way of a novel stem cell framework that mimics the embryonic and fetal developmental environments.

Organoidsmeaning resembling an organare self-assembling 3D cell constructs that recapitulate organ properties and structure to a significant extent, says first author Yonatan Israeli, a graduate student in Aguirres lab.

The innovation deploys a bioengineering process that uses induced pluripotent stem cellsadult cells from a patient to trigger embryonic-like heart development in a dishgenerating a functional mini-heart after a few weeks. The stem cells are obtained from consenting adults and therefore free of ethical concerns.

This process allows the stem cells to develop, basically as they would in an embryo, into the various cell types and structures present in the heart, Aguirre says. We give the cells the instructions and they know what they have to do when all the appropriate conditions are met.

Because the organoids followed the natural cardiac embryonic development process, the researchers studied, in real time, the natural growth of an actual fetal human heart.

This technology allows for the creation of numerous hHOs simultaneously with relative ease, contrasting with existing tissue engineering approaches that are expensive, labor intensive and not readily scalable.

One of the primary issues facing the study of fetal heart development and congenital heart defects is access to a developing heart. Researchers have been confined to the use of mammalian models, donated fetal remains, and in vitro cell research to approximate function and development.

Now we can have the best of both worlds, a precise human model to study these diseasesa tiny human heartwithout using fetal material or violating ethical principles. This constitutes a great step forward, Aguirre says.

Whats next? For Aguirre, the process is twofold. First, the heart organoid represents an unprecedented look into the nuts and bolts of how a fetal heart develops.

In the lab, we are currently using heart organoids to model congenital heart diseasethe most common birth defect in humans affecting nearly 1% of the newborn population, Aguirre says. With our heart organoids, we can study the origin of congenital heart disease and find ways to stop it.

And second, while the hHO is complex, it is far from perfect. For the team, improving the final organoid is another key avenue of future research.

The organoids are small models of the fetal heart with representative functional and structural features, Israeli says. They are, however, not as perfect as a human heart yet. That is something we are working toward.

The researchers are excited about the wide-ranging applicability of these miniature hearts. They enable an unprecedented ability to study many other cardiovascular-related diseasesincluding chemotherapy-induced cardiotoxicity and the effect of diabetes, during pregnancy, on the developing fetal heart.

Additional researchers from Michigan State and Washington University in St. Louis contributed to the work.

The American Heart Association and the National Institutes of Health funded the study.

Source: Michigan State University

Original Study DOI: 10.1101/2020.06.25.171611

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First lab-made 'mini-hearts' mimic the real thing - Futurity: Research News

Cardiac Stem Cells Comments Off on First lab-made ‘mini-hearts’ mimic the real thing – Futurity: Research News | August 24th, 2020

Michigan State University researchers have created for the first time a miniature human heart model in the laboratory, complete with all primary heart cell types and a functioning structure of chambers and vascular tissue.

Aitor Aguirre, assistant professor of biomedical engineering at MSUs Institute for Quantitative Health Science and Engineering.

These minihearts constitute incredibly powerful models in which to study all kinds of cardiac disorders with a degree of precision unseen before, said Aitor Aguirre, the studys senior author and assistant professor of biomedical engineering at MSUs Institute for Quantitative Health Science and Engineering.

This study, Generation of Heart Organoids Modeling Early Human Cardiac Development Under Defined Conditions, appears on the bioRxiv preprint server and was funded by grants from the American Heart Association and the National Institutes of Health. In the United States, heart disease is the No. 1 cause of death.

The human heart organoids, or hHOs for short, were created by way of a novel stem cell framework that mimics the embryonic and fetal developmental environments.

Organoids meaning resembling an organ are self-assembling 3D cell constructs that recapitulate organ properties and structure to a significant extent, said Yonatan Israeli, a graduate student in the Aguirre Lab and first author of the study.

The innovation deploys a bioengineering process that uses induced pluripotent stem cells adult cells from a patient to trigger embryonic-like heart development in a dish generating a functional mini heart after a few weeks. The stem cells are obtained from consenting adults and therefore free of ethical concerns.

This process allows the stem cells to develop, basically as they would in an embryo, into the various cell types and structures present in the heart, Aguirre said. We give the cells the instructions and they know what they have to do when all the appropriate conditions are met.

Because the organoids followed the natural cardiac embryonic development process, the researchers studied, in real time, the natural growth of an actual fetal human heart.

This technology allows for the creation of numerous hHOs simultaneously with relative ease, contrasting with existing tissue engineering approaches that are expensive, labor intensive and not readily scalable.

One of the primary issues facing the study of fetal heart development and congenital heart defects is access to a developing heart. Researchers have been confined to the use of mammalian models, donated fetal remains and in vitro cell research to approximate function and development.

Now we can have the best of both worlds, a precise human model to study these diseases a tiny human heart without using fetal material or violating ethical principles. This constitutes a great step forward, Aguirre said.

Whats next? For Aguirre, the process is twofold. First, the heart organoid represents an unprecedented look into the nuts and bolts of how a fetal heart develops.

In the lab, we are currently using heart organoids to model congenital heart disease the most common birth defect in humans affecting nearly 1% of the newborn population, Aguirre said. With our heart organoids, we can study the origin of congenital heart disease and find ways to stop it.

And second, while the hHO is complex, it is far from perfect. For the team, improving the final organoid is another key avenue of future research. The organoids are small models of the fetal heart with representative functional and structural features, Israeli said. They are, however, not as perfect as a human heart yet. That is something we are working toward.

Aguirre and team are excited about the wide-ranging applicability of these miniature hearts. They enable an unprecedented ability to study many other cardiovascular-related diseases from chemotherapy-induced cardiotoxicity to the effect of diabetes, during pregnancy, on the developing fetal heart.

Other researchers involved in this study were Aaron Wasserman, Mitchell Gabalski and Kristen Ball at MSU; and Chao Zhou, Jinyon Zhou and Guangming Ni at Washington University in St. Louis.

(Note for media: Please include a link to the original paper in online coverage: https://www.biorxiv.org/content/10.1101/2020.06.25.171611v2)

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Scientists grow the first functioning mini human heart model - MSUToday

Cardiac Stem Cells Comments Off on Scientists grow the first functioning mini human heart model – MSUToday | August 20th, 2020

Global Stem Cell Therapy Market: Overview

Also called regenerative medicine, stem cell therapy encourages the reparative response of damaged, diseased, or dysfunctional tissue via the use of stem cells and their derivatives. Replacing the practice of organ transplantations, stem cell therapies have eliminated the dependence on availability of donors. Bone marrow transplant is perhaps the most commonly employed stem cell therapy.

Osteoarthritis, cerebral palsy, heart failure, multiple sclerosis and even hearing loss could be treated using stem cell therapies. Doctors have successfully performed stem cell transplants that significantly aid patients fight cancers such as leukemia and other blood-related diseases.

Know the Growth Opportunities in Emerging Markets

Global Stem Cell Therapy Market: Key Trends

The key factors influencing the growth of the global stem cell therapy market are increasing funds in the development of new stem lines, the advent of advanced genomic procedures used in stem cell analysis, and greater emphasis on human embryonic stem cells. As the traditional organ transplantations are associated with limitations such as infection, rejection, and immunosuppression along with high reliance on organ donors, the demand for stem cell therapy is likely to soar. The growing deployment of stem cells in the treatment of wounds and damaged skin, scarring, and grafts is another prominent catalyst of the market.

On the contrary, inadequate infrastructural facilities coupled with ethical issues related to embryonic stem cells might impede the growth of the market. However, the ongoing research for the manipulation of stem cells from cord blood cells, bone marrow, and skin for the treatment of ailments including cardiovascular and diabetes will open up new doors for the advancement of the market.

Global Stem Cell Therapy Market: Market Potential

A number of new studies, research projects, and development of novel therapies have come forth in the global market for stem cell therapy. Several of these treatments are in the pipeline, while many others have received approvals by regulatory bodies.

In March 2017, Belgian biotech company TiGenix announced that its cardiac stem cell therapy, AlloCSC-01 has successfully reached its phase I/II with positive results. Subsequently, it has been approved by the U.S. FDA. If this therapy is well- received by the market, nearly 1.9 million AMI patients could be treated through this stem cell therapy.

Another significant development is the granting of a patent to Israel-based Kadimastem Ltd. for its novel stem-cell based technology to be used in the treatment of multiple sclerosis (MS) and other similar conditions of the nervous system. The companys technology used for producing supporting cells in the central nervous system, taken from human stem cells such as myelin-producing cells is also covered in the patent.

The regional analysis covers:

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Global Stem Cell Therapy Market: Regional Outlook

The global market for stem cell therapy can be segmented into Asia Pacific, North America, Latin America, Europe, and the Middle East and Africa. North America emerged as the leading regional market, triggered by the rising incidence of chronic health conditions and government support. Europe also displays significant growth potential, as the benefits of this therapy are increasingly acknowledged.

Asia Pacific is slated for maximum growth, thanks to the massive patient pool, bulk of investments in stem cell therapy projects, and the increasing recognition of growth opportunities in countries such as China, Japan, and India by the leading market players.

Global Stem Cell Therapy Market: Competitive Analysis

Several firms are adopting strategies such as mergers and acquisitions, collaborations, and partnerships, apart from product development with a view to attain a strong foothold in the global market for stem cell therapy.

Some of the major companies operating in the global market for stem cell therapy are RTI Surgical, Inc., MEDIPOST Co., Ltd., Osiris Therapeutics, Inc., NuVasive, Inc., Pharmicell Co., Ltd., Anterogen Co., Ltd., JCR Pharmaceuticals Co., Ltd., and Holostem Terapie Avanzate S.r.l.

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Stem Cell Therapy Market Segmentation, Assessment and Growth Opportunities by Forecast 2025 - Scientect

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August 17, 2020

Denver is known for its relatively mild climate and its four distinct seasons. Its also known for its temperature fluctuations over the course of a day or even hours. But what does that mean for the citys residents and for that matter, the rest of the inhabitants of the continental United States when it comes to temperature extremes?

Thats what Ashley Broadbentwanted to know. Specifically, he wanted to know how populations throughout the United States will experience heat and cold during the 21st century.

So, Broadbent, an assistant research professor in Arizona State Universitys School of Geographical Sciences and Urban Planning, used state-of-the-art modeling tools to analyze how three key variables would affect human exposure to extreme temperatures from the beginning of this century to its end.

He and his collaborator Matei Georgescu, an associate professor in the School of Geographical Sciences and Urban Planning, concentrated on the following three key factors: climate change brought about by greenhouse gas emissions, urban development-induced impacts arising from the growth of cities, and population change in individual cities.

The paper, "The motley drivers of heat and cold exposure in 21st century U.S. cities," was published onlineAug. 17 in the Proceedings of the National Academy of Sciences. It is the first study of its kind to consider population-weighted heat and cold exposure that directly and simultaneously account for greenhouse gas and urban development-induced warming.

Graphic by Alex Davis/ASU Media Relations and Strategic Communications

To describe how these three variables would affect temperatures, and in turn populations, Broadbent, Georgescu and co-author Eric Scott Krayenhoff, assistant professor at the University of Guelph, Ontario, in Canada, used a metric they dubbed person-hours, to describe humans exposure to extreme heat and cold.

Its an intuitive metric, Broadbent said. For example, when one person is exposed to one hour of an extreme temperature, that exposure equals one person-hour of exposure. Likewise, if 10 people are exposed to 10 hours of an extreme temperature, that exposure equals 100 person-hours.

I think this definition is more representative of what people experience, which is what this study is about versus a study that simply communicates temperature changes without any human element attached to it, Broadbent said.

Overall, the researchers found that the average annual heat exposure at the start of this century in the United States was about 5.2 billion person-hours. Assuming a worst-case scenario of peak global warming, population growth and urban development, the annual heat exposure would rise to 150 billion person-hours by the end of the century, a nearly 30-fold increase.

The combined effect of these three drivers will substantially increase the average heat exposure across the United States, but heat exposure is not projected to increase uniformly in all cities across the U.S., Broadbent said. There will be hot spots where heat exposure grows sharply.

To that end, the researchers defined heat thresholds based on local city definitions, something previous studies have not done. Instead, prior studies have used fixed-temperature thresholds that may be inappropriate for some cities. Afterall, a 90-degree day in Phoenix feels much different than a 90-degree day in New York City, given relative humidity differences.

Its well-known that cities have locally defined thresholds where heat and cold cause mortality and morbidity, Broadbent explained. In other words, people die at different temperatures in different cities because what is extreme in one city may be normal in another.

Importantly, areas of the United States where human exposure would increase the most is where climate change and population increase in tandem. Meanwhile, urban development has a smaller, yet not negligible effect.

According to the results of the study, the largest absolute changes in population heat exposure are projected to occur in major U.S. metropolitan regions, such as New York, Los Angeles and Atlanta.

The study also finds the largest relativechanges in person-hours related to heat exposure are projected to occur in rapidly growing cities located in the Sun Belt, including Austin, Texas; Orlando, Florida; and Atlanta.

The increase in exposure is quite large if you look at it relative to the start of the century, Broadbent said. Some cities across the Sun Belt, according to our projections, will have 90 times the number of person-hours of heat exposure. For example, cities in Texas that see substantial population growth and strong greenhouse gas-induced climate warming could be markedly affected.

One way to prepare for increased heat exposure is to reduce greenhouse gas emissions on a global scale, which would reduce the number of hours people are exposed to extreme temperatures. Other options include localized infrastructure adaptation that provides buffering effects against rising temperatures such as planting trees, providing shade and cooling areas and constructing buildings using materials that absorb less heat.

Although the average temperature in the United States will be warmer in the future, the study finds that cold exposure will increase slightly compared with the start of the century, primarily because of population growth. While there is a generaldecreasein the number of projected extreme cold events by the end of this century, the number of individuals exposed to extreme cold is projected toincrease,as population growth means that the total number of person-hours of cold exposure will go up, Broadbent said.

Cold is currently more of a national health problem than heat, but our results suggest that by the end of the century heat exposure may become a larger health problem than cold exposure, Broadbent said. However, cold exposure will not disappear completely as the climate warms. In fact, according to one of the teams simulations, Denver is projected to have more extreme cold at the end of the century compared with the beginning, according to the study.

Thats the interesting thing about climate change. We know the average temperature is going to increase, said Broadbent. But we know less about how the extremes are going to change, and often the extremes are the most important part of our daily lives.

There are several takeaway messages from this work, but one of the central ones concerns the future resiliency of our cities, Georgescu said.

The successful steps taken will require holistic thinking that embraces contributions from urban planners, engineers, social scientists and climate scientists with a long-range vision of how we want our cities to be.

"We therefore call on cities to start asking some very foundational questions regarding the projected exposure of their constituents to future environmental change," Georgescu said. "Is the work of the urban climate modeling community being integrated into their environmental adaptation plans? If so, how, and if not, why not?

This work was funded by the National Science Foundation.

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ASU engineers get to the heart of organs-on-a-chip - ASU Now

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DUBLIN--(BUSINESS WIRE)--The "Dilated Cardiomyopathy (DCM) - Market Insights, Epidemiology and Market Forecast - 2030" drug pipelines report has been added to ResearchAndMarkets.com's offering.

This report delivers an in-depth understanding of the Dilated Cardiomyopathy, historical and forecasted epidemiology as well as the Dilated Cardiomyopathy market trends in the United States, EU5 (Germany, France, Italy, Spain, and United Kingdom), and Japan.

The Dilated Cardiomyopathy market report provides current treatment practices, emerging drugs, Dilated Cardiomyopathy market share of the individual therapies, current and forecasted Dilated Cardiomyopathy market size from 2017 to 2030 segmented by seven major markets. The report also covers current Dilated Cardiomyopathy treatment practice/algorithm, market drivers, market barriers and unmet medical needs to curate best of the opportunities and assesses underlying potential of the market.

Epidemiology

The Dilated Cardiomyopathy epidemiology division provides the insights about historical and current Dilated Cardiomyopathy patient pool and forecasted trend for each seven major countries. It helps to recognize the causes of current and forecasted trends by exploring numerous studies and views of key opinion leaders. This part of the report also provides the diagnosed patient pool and their trends along with assumptions undertaken.

The disease epidemiology covered in the report provides historical as well as forecasted Dilated Cardiomyopathy epidemiology segmented as [Total Prevalent Population of Dilated Cardiomyopathy, Total Diagnosed Population of Dilated Cardiomyopathy, Familial and non-familial cases of Dilated Cardiomyopathy, Gender-Specific Cases of Dilated Cardiomyopathy, and Total Treated Cases of Dilated Cardiomyopathy] scenario of Dilated Cardiomyopathy in the 7MM covering the United States, EU5 countries (Germany, France, Italy, Spain, and United Kingdom), and Japan from 2017 to 2030.

Key Findings

Drug Chapters

Drug chapter segment of the Dilated Cardiomyopathy report encloses the detailed analysis of Dilated Cardiomyopathy marketed drugs and late stage (Phase-III and Phase-II) pipeline drugs. It also helps to understand the Dilated Cardiomyopathy clinical trial details, expressive pharmacological action, agreements and collaborations, approval and patent details, advantages and disadvantages of each included drug and the latest news and press releases.

Approved Drug

Corlanor (ivabradine): Amgen

Corlanor (ivabradine) is a hyperpolarization-activated cyclic nucleotide-gated channel blocker that reduces the spontaneous pacemaker activity of the cardiac sinus node by selectively inhibiting the If current, resulting in heart rate reduction with no effect on ventricular repolarization and no effects on myocardial contractility.

The US FDA approval of Corlanor (ivabradine) for the treatment of stable symptomatic heart failure (HF) due to dilated cardiomyopathy in pediatric patients aged 6 months to 18 years was based on a randomized, double-blind, placebo-controlled trial in 116 patients aged 6 months to less than 18 years with symptomatic DCM in sinus rhythm, NYHA/Ross class II to IV HF, and left ventricular ejection fraction 45%. The primary endpoint of the study was 20% reduction in resting heart rate from baseline without bradycardia or symptoms after an initial titration period.

Emerging Drugs

PF-07265803/ARRY-371797/ARRY-797: Pfizer

ARRY-371797 which is also known as ARRY-797 is an oral, p38 mitogen activated protein kinase (MAPK) inhibitor discovered by Array scientists. Compared to other p38 MAPK inhibitors ARRY-797 has unique and differentiated properties: it is highly selective, retains exceptional potency in whole blood and possesses a favorable pharmacokinetic profile. It is currently under phase III trial for the treatment of patients affected with dilated cardiomyopathy due to a Lamin A/C gene mutation. In the year 2019, Pfizer completed the acquisition of Array Biopharma to expand its pipeline and currently this drug is in phase III pipeline drugs of Pfizer with name PF-07265803 for the treatment of patients affected by dilated cardiomyopathy.

Ixmyelocel-T: Vericel

Ixmyelocel-T is an investigational autologous expanded multicellular therapy manufactured from the patient's own bone marrow using Vericel's proprietary, highly automated, fully closed cell-processing system. This process selectively expands the population of mesenchymal stromal cells and alternatively activated macrophages, which are responsible for production of anti-inflammatory and pro-angiogenic factors known to be important for repair of damaged tissue. Ixmyelocel-T has been designated as an orphan drug by the U.S. Food and Drug Administration for use in the treatment of DCM. However, currently the development of this drug is at halt because as per the recent news the company do not have current plans to initiate or fund a phase III trial for this drug at their own.

BC007: Berlin Cures GmbH

BC007 is a DNA aptamer-based compound that binds to and eliminates pathogenic autoantibodies directed against the beta-1 adrenoceptor, a receptor belonging to the large family of cell surface receptors known as G-protein coupled receptors that regulate the heart's rate and contraction strength.

Ifetroban: Cumberland Pharmaceuticals

Ifetroban is a potent and selective inhibitor of the thromboxane receptor (TPr), preventing fibrosis and an inflammatory response. It was initially developed by Bristol-Myers Squibb as an anti-platelet agent to prevent blood clots (blood thrombus), and was acquired by Cumberland in 2011. It is believed that this drug molecule is able to stop important molecular signals that mediate inflammation and fibrosis (tissue scaring) mechanisms in the heart, triggered by the loss of dystrophin protein.

Danicamtiv/MYK-491: MyoKardia

MYK-491 is an orally-administered small molecule designed to increase the number of myosin-actin cross-bridges formed during cardiac muscle contraction while having minimal impact on diastolic function. In the heart, myosin is the motor protein that binds to actin to generate the force and movement of contraction. In patients with dilated cardiomyopathy and systolic heart failure, in which the left ventricle of the heart is too distended and weak to adequately pump blood to meet the body's needs, MYK-491 is intended to increase myosin-actin engagement, thereby targeting the biomechanical defects underlying disease and improving cardiac contractility.

CAP-1002: Capricor Therapeutics

CAP-1002, Capricor's lead product candidate, is a proprietary allogeneic adult stem cell therapy for the treatment of heart disease. The product is derived from donor heart tissue. The cells are expanded in the laboratory using a specialized process and then introduced directly into a patient's heart via infusion into a coronary artery using standard cardiac catheterization techniques. CAP-1002 consists of allogeneic cardiosphere-derived cells, or CDCs, a unique population of cells that has been shown to exert potent immunomodulatory activity and alters the immune system's activity to encourage cellular regeneration.

Market Outlook

Besides treating any recognizable and reversible underlying causes, the management and treatment of DCM are in concordance with the standard heart failure guidelines. Currently, the treatment pattern of DCM is mainly dependent on pharmacological therapy, pacing therapy, surgical options, and Corlanor (ivabradine).

The pharmacological therapies consist of diuretics, inotropic agents, afterload reducing agents, beta-blockers, anticoagulation medications, anti-arrhythmia medications. The main diuretics that are prescribed for the treatment are furosemide, spironolactone, bumetanide, and metolazone. Common side effects of diuretics include dehydration and abnormalities in the blood chemistries particularly potassium loss. Inotopric agents that are prescribed for the treatment are digoxin, dobutamine, dopamine, epinephrine, norepinephrine, vasopressin, and milrinone. Some afterload reducing medications include angiotensin-converting enzyme inhibitors (ACE inhibitors) such as captopril, enalMay, lisinopril, monopril, angiotensin I blocker such as losartan. Losartan and milrinone are inotropic agents that also relax the arteries. Stronger anticoagulation drugs are warfarin, heparin, and enoxaparin; these drugs require careful monitoring with regular blood testing.

Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) have shown benefit in the treatment of heart failure with reduced ejection fraction and are suggested for the patients affected with DCM. Aldosterone receptor blockade with spironolactone or eplerenone also is recommended in patients with New York Heart Association (NYHA) heart failure class II-IV and systolic dysfunction. Similarly, beta-blockade with carvedilol, bisoprolol, or long-acting metoprolol is recommended in all patients with heart failure with reduced ejection fraction without any contraindications. The addition of isosorbide dinitrate plus hydralazine also has shown to increase survival amongst those with advanced disease.

In some cases, beta-blockers allow an enlarged heart to become more normal in size. Common beta-blockers include carvedilol, metoprolol, propranolol, and atenolol. Side effects include dizziness, low heart rate, low blood pressure, and, in some cases, fluid retention, fatigue, impaired school performance, and depression. The choice of anticoagulation drugs depends on how likely it is that a blood clot will form. Less strong anticoagulation medications include aspirin and dipyridamole. Common anti-arrhythmia medications include amiodarone, procainamide, and lidocaine. Also, Corlanor (ivabradine) is an approved therapy for the treatment of 6 months to 18 years old patient affected by Dilated Cardiomyopathy.

Key Findings

According to the report, Dilated Cardiomyopathy market in the 7MM is expected to change in the study period 2017-2030. The total therapeutic market of Dilated Cardiomyopathy in seven major markets was found to be USD 244 million in 2017 which is expected to increase during the study period (2017-2030).

The United States Market Outlook

In 2017, the total market size of Dilated Cardiomyopathy therapies was estimated to be USD 142.9 million in the United States which is expected to increase in the study period (2017-2030).

EU5 Countries: Market Outlook

In 2017, the total market size of Dilated Cardiomyopathy therapies was found to be USD 74.4 million in the EU5 countries which is expected to increase in the study period (2017-2030).

Japan Market Outlook

The total market size of Dilated Cardiomyopathy therapies in Japan was found to be USD 27.1 million in 2017 which is also expected to increase during the study period (2017-2030).

Pipeline Development Activities

The drugs which are in pipeline include:

1. PF-07265803/ARRY-371797/ARRY-797: Pfizer

2. Ixmyelocel-T: Vericel

3. BC007: Berlin Cures GmbH

4. Ifetroban: Cumberland Pharmaceuticals

5. Danicamtiv/MYK-491: MyoKardia

6. CAP-1002: Capricor Therapeutics

Access and Reimbursement Scenario

The record published in United HealthCare Services, in the United States, stated that reimbursement is eligible for the CPT codes related to various genetic testing for cardiac disease. CPT code 81439 includes indications such as hereditary cardiomyopathy (e.g., hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy), genomic sequence analysis panel - must include sequencing of at least five cardiomyopathy-related genes (e.g., DSG2, MYBPC3, MYH7, PKP2, TTN). Moreover, cardiomyopathies that present primarily as neuromuscular disorders and related genetic testing are also covered in the Medical Policy.

KOL Views

To keep up with current market trends, we take KOL's and SME's opinion working in Dilated Cardiomyopathy domain through primary research to fill the data gaps and validates our secondary research. Their opinion helps to understand and validate current and emerging therapies treatment patterns and Dilated Cardiomyopathy market trend. This will support the clients in the introduction of potential upcoming novel treatment by identifying the overall scenario of the market and the unmet needs.

Competitive Intelligence Analysis

The publisher performs Competitive and Market Intelligence analysis of the Dilated Cardiomyopathy Market by using various Competitive Intelligence tools that includes - SWOT analysis, PESTLE analysis, Porter's five forces, BCG Matrix, Market entry strategies etc. The inclusion of the analysis entirely depends upon the data availability.

Scope of the Report

Report Highlights

Companies Mentioned

For more information about this drug pipelines report visit https://www.researchandmarkets.com/r/qfjown

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Worldwide Dilated Cardiomyopathy (DCM) Market Insights, Epidemiology and Forecast - 2030 - ResearchAndMarkets.com - Business Wire

Cardiac Stem Cells Comments Off on Worldwide Dilated Cardiomyopathy (DCM) Market Insights, Epidemiology and Forecast – 2030 – ResearchAndMarkets.com – Business Wire | August 20th, 2020

Global Exosome Therapeutic Market By Type (Natural Exosomes, Hybrid Exosomes), Source (Dendritic Cells, Mesenchymal Stem Cells, Blood, Milk, Body Fluids, Saliva, Urine Others), Therapy (Immunotherapy, Gene Therapy, Chemotherapy), Transporting Capacity (Bio Macromolecules, Small Molecules), Application (Oncology, Neurology, Metabolic Disorders, Cardiac Disorders, Blood Disorders, Inflammatory Disorders, Gynecology Disorders, Organ Transplantation, Others), Route of administration (Oral, Parenteral), End User (Hospitals, Diagnostic Centers, Research & Academic Institutes), Geography (North America, Europe, Asia-Pacific and Latin America)

Exosome therapeutic market is expected to gain market growth in the forecast period of 2019 to 2026. Data Bridge Market Research analyses that the market is growing with a CAGR of 21.9% in the forecast period of 2019 to 2026 and expected to reach USD 31,691.52 million by 2026 from USD 6,500.00 million in 2018. Increasing prevalence of lyme disease, chronic inflammation, autoimmune disease and other chronic degenerative diseases are the factors for the market growth.

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Increased number of exosome therapeutics as compared to the past few years will accelerate the market growth. Companies are receiving funding for exosome therapeutic research and clinical trials. For instance, In September 2018, EXOCOBIO has raised USD 27 million in its series B funding. The company has raised USD 46 million as series a funding in April 2017. The series B funding will help the company to set up GMP-compliant exosome industrial facilities to enhance production of exosomes to commercialize in cosmetics and pharmaceutical industry.

This exosome therapeutic market report provides details of market share, new developments, and product pipeline analysis, impact of domestic and localised market players, analyses opportunities in terms of emerging revenue pockets, changes in market regulations, product approvals, strategic decisions, product launches, geographic expansions, and technological innovations in the market. To understand the analysis and the market scenario contact us for an Analyst Brief, our team will help you create a revenue impact solution to achieve your desired goal.

Increasing demand for anti-aging therapies will also drive the market. Unmet medical needs such as very few therapeutic are approved by the regulatory authority for the treatment in comparison to the demand in global exosome therapeutics market will hamper the market growth market. Availability of various exosome isolation and purification techniques is further creates new opportunities for exosome therapeutics as they will help company in isolation and purification of exosomes from dendritic cells, mesenchymal stem cells, blood, milk, body fluids, saliva, and urine and from others sources. Such policies support exosome therapeutic market growth in the forecast period to 2019-2026.

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Exosome is an extracellular vesicle which is released from cells, particularly from stem cells. Exosome functions as vehicle for particular proteins and genetic information and other cells. Exosome plays a vital role in the rejuvenation and communication of all the cells in our body while not themselves being cells at all. Research has projected that communication between cells is significant in maintenance of healthy cellular terrain. Chronic disease, age, genetic disorders and environmental factors can affect stem cells communication with other cells and can lead to distribution in the healing process.

The growth of the global exosome therapeutic market reflects global and country-wide increase in prevalence of autoimmune disease, chronic inflammation, Lyme disease and chronic degenerative diseases, along with increasing demand for anti-aging therapies. Additionally major factors expected to contribute in growth of the global exosome therapeutic market in future are emerging therapeutic value of exosome, availability of various exosome isolation and purification techniques, technological advancements in exosome and rising healthcare infrastructure.

The major players covered in the report are evox THERAPEUTICS, EXOCOBIO, Exopharm, AEGLE Therapeutics, United Therapeutics Corporation, Codiak BioSciences, Jazz Pharmaceuticals, Inc., Boehringer Ingelheim International GmbH, ReNeuron Group plc, Capricor Therapeutics, Avalon Globocare Corp., CREATIVE MEDICAL TECHNOLOGY HOLDINGS INC., Stem Cells Group among other players domestic and global. Exosome therapeutic market share data is available for Global, North America, Europe, Asia-Pacific, and Latin America separately. DBMR analysts understand competitive strengths and provide competitive analysis for each competitor separately.

The country section of the report also provides individual market impacting factors and changes in regulation in the market domestically that impacts the current and future trends of the market. Data points such as new sales, replacement sales, country demographics, regulatory acts and import-export tariffs are some of the major pointers used to forecast the market scenario for individual countries. Also, presence and availability of global brands and their challenges faced due to large or scarce competition from local and domestic brands, impact of sales channels are considered while providing forecast analysis of the country data.

Read [emailprotected] https://www.databridgemarketresearch.com/reports/global-exosome-therapeutic-market?DW

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Exosome Therapeutic Market (Covid 19 Impact Analysis) Data Highlighting Major Vendors, Promising Regions, Anticipated Growth Forecast To 2027 -...

Cardiac Stem Cells Comments Off on Exosome Therapeutic Market (Covid 19 Impact Analysis) Data Highlighting Major Vendors, Promising Regions, Anticipated Growth Forecast To 2027 -… | August 19th, 2020

CAMBRIDGE, Mass.--(BUSINESS WIRE)--bluebird bio, Inc. (Nasdaq: BLUE) today announced that new data from the clinical development program for its investigational elivaldogene autotemcel (eli-cel, Lenti-D) gene therapy in patients with cerebral adrenoleukodystrophy (CALD), including data from the Phase 2/3 Starbeam study (ALD-102) and available data from the Phase 3 ALD-104 study, will be presented at the 46th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT 2020), taking place virtually from August 29 - September 1, 2020.

New Cerebral Adrenoleukodystrophy (CALD) Data at EBMT 2020

Lenti-D hematopoietic stem cell gene therapy stabilizes neurologic function in boys with cerebral adrenoleukodystrophy (ALD-102 and ALD-104)Presenting Author: Dr. Jrn-Sven Khl, Department of Pediatric Oncology, Hematology and Hemostaseology, Center for Womens and Childrens Medicine, University Hospital LeipzigPoster Session & Number: Gene Therapy; ePoster O077

Additional bluebird bio data at EBMT 2020 includes encore presentations from the companys CALD, sickle cell disease (SCD), transfusion-dependent -thalassemia (TDT) and multiple myeloma programs.

Cerebral Adrenoleukodystrophy (CALD) Encore Data at EBMT 2020

Outcomes of allogeneic hematopoietic stem cell transplant in patients with cerebral adrenoleukodystrophy vary by donor cell source, conditioning regimen, and stage of cerebral disease status (ALD-103)Presenting Author: Dr. Jaap Jan Boelens, Chief, Pediatric Stem Cell Transplantation and Cellular Therapies Service, Memorial Sloan Kettering Cancer CenterPoster Session & Number: Haemoglobinopathy and inborn errors; ePoster O106

Multiple Myeloma Correlative Encore Data at EBMT 2020

Markers of initial and long-term responses to idecabtagene vicleucel (ide-cel; bb2121) in the CRB-401 study in relapsed/refractory multiple myelomaPresenting Author: Dr. Ethan G. Thompson, Bristol Myers SquibbPoster Session & Number: CAR-based Cellular Therapy clinical; ePoster A089

Sickle Cell Disease (SCD) Encore Data at EBMT 2020

LentiGlobin for sickle cell disease (SCD) gene therapy (GT): updated results in Group C patients from the Phase 1/2 HGB-206 studyPresenting Author: Dr. Markus Y. Mapara, Director, Adult Blood and Marrow Transplantation Program, Columbia University Medical CenterOral Session & Number: Inborn Errors; O080Date & Time: September 1, 2020; 4:35 4:42 PM CET/10:35 10:42 AM ET

Transfusion-Dependent -Thalassemia (TDT) Encore Data at EBMT 2020

Clinical outcomes following autologous hematopoietic stem cell transplantation with LentiGlobin gene therapy in the Phase 3 Northstar-2 and Northstar-3 studies for transfusion-dependent -thalassemiaPresenting Author: Professor Franco Locatelli, Director, Department of Pediatric Hematology and Oncology, Ospedale Pediatrico Bambino GesPoster Session & Number: Gene Therapy; ePoster O074

LentiGlobin gene therapy treatment of two patients with transfusion-dependent -thalassemia (case report)Presenting Author: Dr. Mattia Algeri, Department of Pediatric Oncohematology - Transplantation Unit and Cell Therapies, Ospedale Pediatrico Bambino GesPoster Session & Number: Haemoglobinopathy and inborn errors; ePoster A328

Cross Indication Encore Data at EBMT 2020

Safety of autologous hematopoietic stem cell transplantation with gene addition therapy for transfusion-dependent -thalassemia, sickle cell disease, and cerebral adrenoleukodystrophyPresenting Author: Dr. Evangelia Yannaki, Director, Gene and Cell Therapy Center, Hematology Department, George Papanicolaou HospitalPoster Session & Number: Gene Therapy; ePoster O078

Abstracts outlining bluebird bios accepted data at EBMT 2020 are available on the Annual Meeting website. On August 29, 2020, at 12:30 PM CET/6:30 AM ET, the embargo will lift for ePosters and oral presentations accepted for EBMT 2020. Presentations will be available for virtual viewing throughout the duration of the live meeting and content will be accessible online following the close of the meeting until November 1, 2020.

About elivaldogene autotemcel (eli-cel, Lenti-D gene therapy)In July 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) granted an accelerated assessment to eli-cel gene therapy for cerebral adrenoleukodystrophy (CALD). bluebird bio is currently on track to submit the Marketing Authorization Application (MAA) in the EU for eli-cel for CALD by year-end 2020, and the Biologics License Application (BLA) in the U.S. in mid-2021.

bluebird bio is currently enrolling patients for a Phase 3 study (ALD-104) designed to assess the efficacy and safety of eli-cel after myeloablative conditioning using busulfan and fludarabine in patients with CALD. Contact clinicaltrials@bluebirdbio.com for more information and a list of study sites.

Additionally, bluebird bio is conducting a long-term safety and efficacy follow-up study (LTF-304) for patients who have been treated with eli-cel for CALD and completed two years of follow-up in bluebird bio-sponsored studies.

The Phase 2/3 Starbeam study (ALD-102) has completed enrollment. For more information about the ALD-102 study visit: http://www.bluebirdbio.com/our-science/clinical-trials or clinicaltrials.gov and use identifier NCT01896102.

Adrenoleukodystrophy (ALD) is a rare, X-linked metabolic disorder that is estimated to affect one in 21,000 male newborns worldwide. Approximately 40 percent of boys with ALD will develop CALD, the most severe form of ALD. CALD is a progressive neurogenerative disease that involves breakdown of myelin, the protective sheath of the nerve cells in the brain that are responsible for thinking and muscle control. Symptoms of CALD usually occur in early childhood and progress rapidly, if untreated, leading to severe loss of neurologic function, and eventual death, in most patients.

The European Medicines Agency (EMA) accepted eli-cel gene therapy for the treatment of CALD into its Priorities Medicines scheme (PRIME) in July 2018, and previously granted Orphan Medicinal Product designation to eli-cel.

The U.S. Food and Drug Administration (FDA) granted eli-cel Orphan Drug status, Rare Pediatric Disease designation, and Breakthrough Therapy designation for the treatment of CALD.

Eli-cel is not approved for any indication in any geography.

About idecabtagene vicleucel (ide-cel; bb2121)Ide-cel is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor (CAR) T cell immunotherapy. The ide-cel CAR is comprised of a murine extracellular single-chain variable fragment (scFv) specific for recognizing BCMA, attached to a human CD8 hinge and transmembrane domain fused to the T cell cytoplasmic signaling domains of CD137 4-1BB and CD3- chain, in tandem. Ide-cel recognizes and binds to BCMA on the surface of multiple myeloma cells leading to CAR T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.

In addition to the pivotal KarMMa trial evaluating ide-cel in patients with relapsed and refractory multiple myeloma, bluebird bio and Bristol Myers Squibbs broad clinical development program for ide-cel includes clinical studies (KarMMa-2, KarMMa-3, KarMMa-4) in earlier lines of treatment for patients with multiple myeloma, including newly diagnosed multiple myeloma. For more information visit clinicaltrials.gov.

In July 2020, Bristol Myers Squibb (BMS) and bluebird bio submitted the Biologics License Application for ide-cel to the U.S. Food and Drug Administration for the treatment of adult patients with multiple myeloma who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody. Ide-cel is the first CAR T cell therapy submitted for regulatory review to target BCMA and for multiple myeloma.

Ide-cel was granted Breakthrough Therapy Designation (BTD) by the U.S. Food and Drug Administration (FDA) and PRIority Medicines (PRIME) designation, as well as Accelerated Assessment status, by the European Medicines Agency for relapsed and refractory multiple myeloma.

Ide-cel is being developed as part of a Co-Development, Co-Promotion and Profit Share Agreement between BMS and bluebird bio.

Ide-cel is not approved for any indication in any geography.

About LentiGlobin for Sickle Cell DiseaseLentiGlobin for sickle cell disease (SCD) is an investigational gene therapy being studied as a potential treatment for SCD. bluebird bios clinical development program for LentiGlobin for SCD includes the ongoing Phase 1/2 HGB-206 study and the ongoing Phase 3 HGB-210 study.

bluebird bio is conducting a long-term safety and efficacy follow-up study (LTF-303) for people who have participated in bluebird bio-sponsored clinical studies of betibeglogene autotemcel and LentiGlobin for SCD. For more information visit: https://www.bluebirdbio.com/our-science/clinical-trials or clinicaltrials.gov and use identifier NCT02633943 for LTF-303.

SCD is a serious, progressive and debilitating genetic disease caused by a mutation in the -globin gene that leads to the production of abnormal sickle hemoglobin (HbS). HbS causes red blood cells (RBCs) to become sickled and fragile, resulting in chronic hemolytic anemia, vasculopathy and painful vaso-occlusive crises (VOCs). For adults and children living with SCD, this means painful crises and other life-altering or life-threatening acute complicationssuch as acute chest syndrome (ACS), stroke and infections. If patients survive the acute complications, vasculopathy and end-organ damage, resulting complications can lead to pulmonary hypertension, renal failure and early death; in the U.S. the median age of death for someone with sickle cell disease is 43 - 46 years.

LentiGlobin for SCD received Orphan Medicinal Product designation from the European Commission for the treatment of SCD.

The U.S. Food and Drug Administration (FDA) granted Orphan Drug status and Regenerative Medicine Advanced Therapy (RMAT) designation and rare pediatric disease designation for LentiGlobin for the treatment of SCD.

bluebird bio reached general agreement with the U.S. Food and Drug Administration (FDA) that the clinical data package required to support a Biologics Licensing Application (BLA) submission for LentiGlobin for SCD will be based on data from a portion of patients in the HGB-206 study Group C that have already been treated. The planned submission will be based on an analysis using complete resolution of severe vaso-occlusive events (VOEs) as the primary endpoint with at least 18 months of follow-up post-treatment with LentiGlobin for SCD. Globin response will be used as a key secondary endpoint.

bluebird bio anticipates additional guidance from the FDA regarding the commercial manufacturing process, including suspension lentiviral vector. bluebird bio announced in a May 11, 2020 press release it plans to seek an accelerated approval and expects to submit the U.S. BLA for SCD in the second half of 2021.

LentiGlobin for SCD is investigational and has not been approved in any geography.

About betibeglogene autotemcel (beti-cel; formerly LentiGlobin gene therapy for -thalassemia)The European Commission granted conditional marketing authorization (CMA) for betibeglogene autotemcel, marketed as ZYNTEGLO gene therapy, for patients 12 years and older with transfusion-dependent -thalassemia (TDT) who do not have a 0/0 genotype, for whom hematopoietic stem cell (HSC) transplantation is appropriate, but a human leukocyte antigen (HLA)-matched related HSC donor is not available. On April 28, 2020, the European Medicines Agency (EMA) renewed the CMA for ZYNTEGLO, supported by data from 32 patients treated with ZYNTEGLO, including three patients with up to five years of follow-up.

In the HGB-207 clinical study supporting the conditional marketing approval of ZYNTEGLO, the primary endpoint was transfusion independence (TI) by Month 24, defined as a weighted average Hb 9 g/Dl without any RBC transfusions for a continuous period of 12 months at any time during the study after infusion of ZYNTEGLO. Ten patients were evaluable for assessment of TI. Of these, 9/10 (90.0%, 95% CI 55.5-99.7%) achieved TI at last follow-up. Among these nine patients, the median (min, max) weighted average Hb during TI was 12.22 (11.4, 12.8) g/dLl.

TDT is a severe genetic disease caused by mutations in the -globin gene that result in reduced or significantly reduced hemoglobin (Hb). In order to survive, people with TDT maintain Hb levels through lifelong chronic blood transfusions. These transfusions carry the risk of progressive multi-organ damage due to unavoidable iron overload.

Beti-cel adds functional copies of a modified form of the -globin gene (A-T87Q-globin gene) into a patients own hematopoietic (blood) stem cells (HSCs). Once a patient has the A-T87Q-globin gene, they have the potential to produce HbAT87Q, which is gene therapy-derived hemoglobin, at levels that may eliminate or significantly reduce the need for transfusions.

Non-serious adverse events (AEs) observed during the clinical studies that were attributed to betibeglogene autotemcel included abdominal pain, thrombocytopenia, leukopenia, neutropenia, hot flush, dyspnoea, pain in extremity, and non-cardiac chest pain. Two serious adverse events (SAE) of thrombocytopenia were considered possibly related to beti-cel.

Additional AEs observed in clinical studies were consistent with the known side effects of HSC collection and bone marrow ablation with busulfan, including SAEs of veno-occlusive disease.

The CMA for beti-cel is valid in the 27 member states of the EU as well as UK, Iceland, Liechtenstein and Norway. For details, please see the Summary of Product Characteristics (SmPC).

The U.S. Food and Drug Administration granted beti-cel Orphan Drug status and Breakthrough Therapy designation for the treatment of TDT. Beti-cel is not approved in the United States.

Beti-cel continues to be evaluated in the ongoing Phase 3 Northstar-2 and Northstar-3 studies. For more information about the ongoing clinical studies, visit http://www.northstarclinicalstudies.com or clinicaltrials.gov and use identifier NCT02906202 for Northstar-2 (HGB-207), NCT03207009 for Northstar-3 (HGB-212).

About bluebird bio, Inc.bluebird bio is pioneering gene therapy with purpose. From our Cambridge, Mass., headquarters, were developing gene therapies for severe genetic diseases and cancer, with the goal that people facing potentially fatal conditions with limited treatment options can live their lives fully. Beyond our labs, were working to positively disrupt the healthcare system to create access, transparency and education so that gene therapy can become available to all those who can benefit.

bluebird bio is a human company powered by human stories. Were putting our care and expertise to work across a spectrum of disorders including cerebral adrenoleukodystrophy, sickle cell disease, -thalassemia and multiple myeloma, using three gene therapy technologies: gene addition, cell therapy and (megaTAL-enabled) gene editing.

bluebird bio has additional nests in Seattle, Wash.; Durham, N.C.; and Zug, Switzerland. For more information, visit bluebirdbio.com.

Follow bluebird bio on social media: @bluebirdbio, LinkedIn, Instagram and YouTube.

Lenti-D and bluebird bio are trademarks of bluebird bio, Inc.

Forward-Looking StatementsThis release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements regarding the companys financial condition, results of operations, as well as statements regarding the plans for regulatory submissions for beti-cel (marketed as ZYTENGLO in the European Union), eli-cel, ide-cel, and LentiGlobin for SCD, including anticipated endpoints to support regulatory submissions and timing expectations; the companys expectations regarding the potential for the suspension manufacturing process for lentiviral vector; its expectations for commercialization efforts for ZYNTEGLO in Europe; as well as the companys intentions regarding the timing for providing further updates on the development and commercialization of ZYNTEGLO and the companys product candidates. Any forward-looking statements are based on managements current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, the risks that the COVID-19 pandemic and resulting economic conditions will have a greater impact on the companys operations and plans than anticipated; that our amended collaboration with BMS will not continue or be successful; that preliminary positive efficacy and safety results from our prior and ongoing clinical trials will not continue or be repeated in our ongoing or future clinical trials; the risk that our plans for submitting a BLA for LentiGlobin for SCD may be delayed if the FDA does not accept our comparability plans for the use of the suspension manufacturing process for lentiviral vector; the risk that the submission of BLA for ide-cel is not accepted for filing by the FDA or approved in the timeline we expect, or at all; the risk of cessation or delay of any of the ongoing or planned clinical studies and/or our development of our product candidates, including due to delays from the COVID-19 pandemics impact on healthcare systems; the risk that the current or planned clinical trials of our product candidates will be insufficient to support regulatory submissions or marketing approval in the United States and European Union; the risk that regulatory authorities will require additional information regarding our product candidates, resulting in delay to our anticipated timelines for regulatory submissions, including our applications for marketing approval; the risk that we will encounter challenges in the commercial launch of ZYNTEGLO in the European Union, including in managing our complex supply chain for the delivery of drug product, in the adoption of value-based payment models, or in obtaining sufficient coverage or reimbursement for our products; and the risk that any one or more of our product candidates, will not be successfully developed, approved or commercialized. For a discussion of other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled Risk Factors in our most recent Form 10-K, as well as discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and bluebird bio undertakes no duty to update this information unless required by law.

Original post:
bluebird bio to Present New Data from Clinical Studies of elivaldogene autotemcel (eli-cel, Lenti-D) Gene Therapy for Cerebral Adrenoleukodystrophy...

Cardiac Stem Cells Comments Off on bluebird bio to Present New Data from Clinical Studies of elivaldogene autotemcel (eli-cel, Lenti-D) Gene Therapy for Cerebral Adrenoleukodystrophy… | August 17th, 2020

Global Stem Cell Therapy Market: Overview

Also called regenerative medicine, stem cell therapy encourages the reparative response of damaged, diseased, or dysfunctional tissue via the use of stem cells and their derivatives. Replacing the practice of organ transplantations, stem cell therapies have eliminated the dependence on availability of donors. Bone marrow transplant is perhaps the most commonly employed stem cell therapy.

Osteoarthritis, cerebral palsy, heart failure, multiple sclerosis and even hearing loss could be treated using stem cell therapies. Doctors have successfully performed stem cell transplants that significantly aid patients fight cancers such as leukemia and other blood-related diseases.

Know the Growth Opportunities in Emerging Markets

Global Stem Cell Therapy Market: Key Trends

The key factors influencing the growth of the global stem cell therapy market are increasing funds in the development of new stem lines, the advent of advanced genomic procedures used in stem cell analysis, and greater emphasis on human embryonic stem cells. As the traditional organ transplantations are associated with limitations such as infection, rejection, and immunosuppression along with high reliance on organ donors, the demand for stem cell therapy is likely to soar. The growing deployment of stem cells in the treatment of wounds and damaged skin, scarring, and grafts is another prominent catalyst of the market.

On the contrary, inadequate infrastructural facilities coupled with ethical issues related to embryonic stem cells might impede the growth of the market. However, the ongoing research for the manipulation of stem cells from cord blood cells, bone marrow, and skin for the treatment of ailments including cardiovascular and diabetes will open up new doors for the advancement of the market.

Global Stem Cell Therapy Market: Market Potential

A number of new studies, research projects, and development of novel therapies have come forth in the global market for stem cell therapy. Several of these treatments are in the pipeline, while many others have received approvals by regulatory bodies.

In March 2017, Belgian biotech company TiGenix announced that its cardiac stem cell therapy, AlloCSC-01 has successfully reached its phase I/II with positive results. Subsequently, it has been approved by the U.S. FDA. If this therapy is well- received by the market, nearly 1.9 million AMI patients could be treated through this stem cell therapy.

Another significant development is the granting of a patent to Israel-based Kadimastem Ltd. for its novel stem-cell based technology to be used in the treatment of multiple sclerosis (MS) and other similar conditions of the nervous system. The companys technology used for producing supporting cells in the central nervous system, taken from human stem cells such as myelin-producing cells is also covered in the patent.

The regional analysis covers:

Order this Report TOC for Detailed Statistics

Global Stem Cell Therapy Market: Regional Outlook

The global market for stem cell therapy can be segmented into Asia Pacific, North America, Latin America, Europe, and the Middle East and Africa. North America emerged as the leading regional market, triggered by the rising incidence of chronic health conditions and government support. Europe also displays significant growth potential, as the benefits of this therapy are increasingly acknowledged.

Asia Pacific is slated for maximum growth, thanks to the massive patient pool, bulk of investments in stem cell therapy projects, and the increasing recognition of growth opportunities in countries such as China, Japan, and India by the leading market players.

Global Stem Cell Therapy Market: Competitive Analysis

Several firms are adopting strategies such as mergers and acquisitions, collaborations, and partnerships, apart from product development with a view to attain a strong foothold in the global market for stem cell therapy.

Some of the major companies operating in the global market for stem cell therapy are RTI Surgical, Inc., MEDIPOST Co., Ltd., Osiris Therapeutics, Inc., NuVasive, Inc., Pharmicell Co., Ltd., Anterogen Co., Ltd., JCR Pharmaceuticals Co., Ltd., and Holostem Terapie Avanzate S.r.l.

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Stem Cell Therapy Market Landscape Assessment By Type and Analysis Current Trends by Forecast To 2025 - The Daily Chronicle

Cardiac Stem Cells Comments Off on Stem Cell Therapy Market Landscape Assessment By Type and Analysis Current Trends by Forecast To 2025 – The Daily Chronicle | August 17th, 2020

Dear EditorExcellent review and so needed and well-timedThe only issue that did not get the attention it needs are the neuropsychiatric symptoms of mild COVID-19. This is important for medical professionals to know, to avoid labeling the patients' problems as psychiatric and even hysterical as some recently did in a major newspaper here in Belgium.There are two sides to the mental sequelae of mild COVID.a) the consequences of the impact of going through a global pandemic, of lockdown, of COVID patients in their immediate environment, of the fear of infection or infecting others, of losing their job, and finally of their own infection.b) the mental symptoms of an organic disorder.In the subject literature about COIVD-19 (and MERS, SARS and other infections) several mechanisms are mentioned.-A direct neurotropic impact of the virus, especially, but not only via ACE2, both in neurons and glial cells, especially targeting the brain stem which plays a role in emotions. and brought there, among other things, via the direct connection of the olfactory bulb.-Inflammatory and immune reactions that result in cognitive and psychiatric symptoms:(the "misty brain" cited by many patients)-Reactions of the autonomic nervous system, eg cardiac arrhythmias can also be very scary.-Alteration of the gas exchange -oxygen nd carbon dioxide- due to damage to the alveoli resulting in a suboptimal pH.These results in mental symptoms of an organic disorder: memory problems, word finding disorders, confusion, major sleeping problems, insecure motor skills, anorexia, etc. and of course very often chronic fatigue, muscle weakness and anxiety.Of course, fear or anger of the patient are amplified when the doctor labels this as purely psychological, while the patient who has never been ill before, clearly experiences its not.

Because we have only known the disease for six months and we still know so little about it, it is therefore better to take the experiences of the patients seriously, instead of brushing them off as purely psychological or psychiatric.

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Re: Management of post-acute covid-19 in primary care - The BMJ

Cardiac Stem Cells Comments Off on Re: Management of post-acute covid-19 in primary care – The BMJ | August 17th, 2020

Shahid Akhter, editor, ETHealthworld, spoke to. Dr A. Velumani, Promoter, Chairman, Managing Director and Chief Executive Officer, Thyrocare Technologies, to know more about the challenges and opportunities associated with Covid diagnostics business.

Covid-19 : ChallengesBecause of the lockdown, the existing non-covid healthcare and diagnostics business collapsed. It collapsed to 2% suddenly within a week and it didn't allow it to resume for three months.Multiple advisory's multiple tests, whom to test and whom not to, along with plenty of show cause notice because a lot of administrators wanted to under-report positivity and some probably wanted the professional gains, so a lot of time they took in the review. These were the challenges but there were a lot of opportunities as well.

Covid-19: LearningsIn my opinion, Lockdown is not the solution, repeating lockdowns, having every different strict guideline for every different state is not the solution. It won't help to reduce. Secondly, Rapid antigen kits are useless, it doesn't solve anything so we've learned the RT-PCR is the most reliable one in the covid diagnosis.Covid-19: Government's InitiativeAlso, the government labs have contributed significantly which wasn't expected, we were all thinking it is just the private labs who are truly scaling up but government labs too scaled up and contributed more in more than 50% of the testing.

Covid-19: Immunity and antibodyImmunity matters, I don't think lockdown can stop Covid. It is the antibodies that can stop the Covid and India is blessed as only 30% tests are there per million whereas in the US there are 600 tests per million. The antibody power is important to be seen as well if not then there is a problem.

Covid-19: Towards a new normalWork from home will continue, even in healthcare, it is just 17% which is working from home. Also, there will be two different religions in healthcare that will be Covid and Non-Covid so that infection will not pass on to one covid patient to another and non-covid will not move to covid hospitals. The spending on hygiene needs to be high because the general population is scared, medical doctors are scared and the patients are scared.

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RT-PCR is the most reliable test in the covid diagnosis: Dr A. Velumani, CEO, Thyrocare Technologies Ltd. - ETHealthworld.com

Cardiac Stem Cells Comments Off on RT-PCR is the most reliable test in the covid diagnosis: Dr A. Velumani, CEO, Thyrocare Technologies Ltd. – ETHealthworld.com | August 17th, 2020

Blocking an enzyme linked with inflammation makes it possible for stem cells to repair damaged heart tissue, new research from UC Davis Health scientists shows.

Researchers Phung Thai (left) and Padmini Sirish were part of a research team seeking stem cell solutions to heart failure care.

The enzyme soluble epoxide hydrolase, or sEH is a known factor in lung and joint disease. Now, it is a focus of heart-disease researchers as well.

The authors expect their work will lead to a new and powerful class of compounds that overcome the cell death and muscle thickening associated with heart failure a common outcome of a heart attack or long-term cardiovascular disease.

The study, conducted in mice, is published in Stem Cells Translational Medicine. The work was led by cardiologist Nipavan Chiamvimonvat.

The science of using stem cell treatments for heart disease has been full of promise but little progress, Chiamvimonvat said. The inflammation that accompanies heart disease is simply not conducive to stem cell survival.

Prior studies show that stem cells transplanted to the heart experience significant attrition in a very short period of time.

We think weve found a way to quiet that inflammatory environment, giving stem cells a chance to survive and do the healing work we know they can do, said lead author and cardiovascular medicine researcher Padmini Sirish.

Heart failure occurs when the heart no longer pumps blood efficiently, reducing oxygen throughout the body. Survival is around 45-60% five years after diagnosis. It affects approximately 5.7 million people in the U.S., with annual costs of nearly $30 billion. By 2030, it could affect as many as 9 million people at a cost of nearly $80 billion.

Chiamvimonvat often treats patients with heart failure and has been frustrated by the lack of effective medications for the disease, especially when it progresses to later stages. The best current therapies for end-stage heart failure are surgical heart transplants or mechanical heart pumps.

She expects her outcome will lead to a two-part treatment for end-stage heart failure that combines an sEH-blocking compound with stem cell transplantation.

Chiamvimonvat and her team tested that theory in mice using cardiac muscle cells known as cardiomyocytes, which were derived from human-induced pluripotent stem cells (hiPSCs). A hiPSC is a cell taken from any human tissue (usually skin or blood) and genetically modified to behave like an embryonic stem cell. They have the ability to form all cell types.

This research was led by cardiologist Nipavan Chiamvimonvat.

The specific sEH inhibitor used in the study TPPU was selected based on the work of co-author and cancer researcher Bruce Hammock, whose lab has provided detailed studies of nearly a dozen of the enzyme inhibitors.

The researchers studied six groups of mice with induced heart attacks. A group treated with a combination of the inhibitor and hiPSCs had the best outcomes in terms of increased engraftment and survival of transplanted stem cells. That group also had less heart muscle thickening and improved cardiac function.

Taken together, our data suggests that conditioning hiPSC cardiomyocytes with sEH inhibitors may help the cells to better survive the harsh conditions in the muscle damaged by a heart attack, Hammock said.

Chiamvimonvat and her team will next test the process in a larger research animal model to provide more insights into the beneficial role of TPPU. She also wants to test the process with additional heart diseases, including atrial fibrillation. Her ultimate goal, in collaboration with Hammock, is to launch human clinical trials to test the safety of the treatment.

It is my dream as a clinician and scientist to take the problems I see in the clinic to the lab for solutions that benefit our patients, Chiamvimonvat said. It is only possible because of the incredible strength of our team and the extraordinarily collaborative nature of research at UC Davis.

Additional co-authors were Phung Thai, Jun Yang, Xiao-Dong Zhang, Lu Ren, Ning Li, Valeriy Timofeyev, Kin Sing Lee, Carol Nader, Douglas Rowland, Sergey Yechikov, Svetlana Ganaga, J. Nilas Young and Deborah Lieu, all from UC Davis.

Their work was funded by the American Heart Association, Harold S. Geneen Charitable Trust. Rosenfeld Heart Foundation, U.S. Department of Veterans Affairs and the National Institutes of Health (grants T32HL86350, F32HL149288, K99R00ES024806, R35ES030443, P42ES04699, IR35 ES0443-1, P01AG051443, R01DC015135, R56HL138392, R01HL085727, R01HL085844, R01HL137228 and S10RR033106).

The study, titled Suppression of Inflammation and Fibrosis using Soluble Epoxide Hydrolase Inhibitors Enhances Cardiac Stem Cell-Based Therapy, is available online.

More information about UC Davis Health, including its cardiovascular medicine and stem cell programs, is at health.ucdavis.edu.

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UC Davis researchers find a way to help stem cells work ...

Cardiac Stem Cells Comments Off on UC Davis researchers find a way to help stem cells work … | August 16th, 2020

London: In a major study, researchers have found that Covid-19 patients with cardiovascular comorbidities or risk factors are more likely to develop heart complications while hospitalised, and more likely to die from the virus.

According to the study, published in the journal PLOS ONE, it is crucial for clinicians working with cardiovascular patients to understand the clinical presentation and risk factors for Covid-19 infection in this group.

"For most people, the Novel Coronavirus Disease 2019 (Covid-19) causes mild illness, however, it can generate severe pneumonia and lead to death in others," said study authors from the Magna Graecia University in Italy.

At the time they were admitted to the hospital, 12.89 per cent of the patients had cardiovascular comorbidities, 36.08 per cent had hypertension and 19.45 per cent had diabetes.

The findings showed that cardiovascular complications were documented during the hospital stay of 14.09 per cent of Covid-19 patients.

According to the researchers, the most common of these complications were arrhythmias or palpitations; significant numbers of patients also had myocardial injury.

Myocardial injury is considered acute if there is a rise and fall of cardiac troponin concentrations exceeding biological and analytical variation.

When the researchers analysed the data, they found that pre-existing cardiovascular comorbidities or risk factors were significant predictors of cardiovascular complications, but age and gender were not.

The study showed that both age and pre-existing cardiovascular comorbidities or risk factors were significant predictors of death.

"Cardiovascular complications are frequent among Covid-19 patients and might contribute to adverse clinical events and mortality," the study author concluded.

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Covid-19 patients with heart problems more likely to die: Study - ETHealthworld.com

Cardiac Stem Cells Comments Off on Covid-19 patients with heart problems more likely to die: Study – ETHealthworld.com | August 16th, 2020

Global Stem Cell Reconstructive Marketwas valued US$ XX Mn in 2019 and is expected to reach US$ XX Mn by 2027, at a CAGR of 24.5% during a forecast period.

Market Dynamics

The Research Report gives an in-depth account of the drivers and restraints in the stem cell reconstructive market. Stem cell reconstructive surgery includes the treatment of injured or dented part of body. Stem cells are undifferentiated biological cells, which divide to produce more stem cells. Growing reconstructive surgeries led by the rising number of limbs elimination and implants and accidents are boosting the growth in the stem cell reconstructive market. Additionally, rising number of aged population, number of patients suffering from chronic diseases, and unceasing development in the technology, these are factors which promoting the growth of the stem cell reconstructive market. Stem cell reconstructive is a procedure containing the use of a patients own adipose tissue to rise the fat volume in the area of reconstruction and therefore helping 3Dimentional reconstruction in patients who have experienced a trauma or in a post-surgical event such as a mastectomy or lumpectomy, brain surgery, or reconstructive surgery as a result of an accident or injury. Stem cell reconstructive surgeries are also used in plastic or cosmetic surgeries as well. Stem cell and regenerative therapies gives many opportunities for development in the practice of medicine and the possibility of an array of novel treatment options for patients experiencing a variety of symptoms and conditions. Stem cell therapy, also recognised as regenerative medicine, promotes the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives.

The common guarantee of all the undifferentiated embryonic stem cells (ESCs), foetal, amniotic, UCB, and adult stem cell types is their indefinite self-renewal capacity and high multilineage differentiation potential that confer them a primitive and dynamic role throughout the developmental process and the lifespan in adult mammal.However, the high expenditure of stem cell reconstructive surgeries and strict regulatory approvals are restraining the market growth.

The report study has analyzed revenue impact of covid-19 pandemic on the sales revenue of market leaders, market followers and disrupters in the report and same is reflected in our analysis.

Global Stem Cell Reconstructive Market Segment analysis

Based on Cell Type, the embryonic stem cells segment is expected to grow at a CAGR of XX% during the forecast period. Embryonic stem cells (ESCs), derived from the blastocyst stage of early mammalian embryos, are distinguished by their capability to distinguish into any embryonic cell type and by their ability to self-renew. Owing to their plasticity and potentially limitless capacity for self-renewal, embryonic stem cell therapies have been suggested for regenerative medicine and tissue replacement after injury or disease. Additionally, their potential in regenerative medicine, embryonic stem cells provide a possible another source of tissue/organs which serves as a possible solution to the donor shortage dilemma. Researchers have differentiated ESCs into dopamine-producing cells with the hope that these neurons could be used in the treatment of Parkinsons disease. Upsurge occurrence of cardiac and malignant diseases is promoting the segment growth. Rapid developments in this vertical contain protocols for directed differentiation, defined culture systems, demonstration of applications in drug screening, establishment of several disease models, and evaluation of therapeutic potential in treating incurable diseases.

Global Stem Cell Reconstructive Market Regional analysis

The North American region has dominated the market with US$ XX Mn. America accounts for the largest and fastest-growing market of stem cell reconstructive because of the huge patient population and well-built healthcare sector. Americas stem cell reconstructive market is segmented into two major regions such as North America and South America. More than 80% of the market is shared by North America due to the presence of the US and Canada.

Europe accounts for the second-largest market which is followed by the Asia Pacific. Germany and UK account for the major share in the European market due to government support for research and development, well-developed technology and high healthcare expenditure have fuelled the growth of the market. This growing occurrence of cancer and diabetes in America is the main boosting factor for the growth of this market.

The objective of the report is to present a comprehensive analysis of the Global Stem Cell Reconstructive Market including all the stakeholders of the industry. The past and current status of the industry with forecasted market size and trends are presented in the report with the analysis of complicated data in simple language. The report covers all the aspects of the industry with a dedicated study of key players that includes market leaders, followers and new entrants. PORTER, SVOR, PESTEL analysis with the potential impact of micro-economic factors of the market has been presented in the report. External as well as internal factors that are supposed to affect the business positively or negatively have been analysed, which will give a clear futuristic view of the industry to the decision-makers.

The report also helps in understanding Global Stem Cell Reconstructive Market dynamics, structure by analysing the market segments and projects the Global Stem Cell Reconstructive Market size. Clear representation of competitive analysis of key players by Application, price, financial position, Product portfolio, growth strategies, and regional presence in the Global Stem Cell Reconstructive Market make the report investors guide.Scope of the Global Stem Cell Reconstructive Market

Global Stem Cell Reconstructive Market, By Sources

Allogeneic Autologouso Bone Marrowo Adipose Tissueo Blood Syngeneic OtherGlobal Stem Cell Reconstructive Market, By Cell Type

Embryonic Stem Cell Adult Stem CellGlobal Stem Cell Reconstructive Market, By Application

Cancer Diabetes Traumatic Skin Defect Severe Burn OtherGlobal Stem Cell Reconstructive Market, By End-User

Hospitals Research Institute OthersGlobal Stem Cell Reconstructive Market, By Regions

North America Europe Asia-Pacific South America Middle East and Africa (MEA)Key Players operating the Global Stem Cell Reconstructive Market

Osiris Therapeutics NuVasives Cytori Therapeutics Takeda (TiGenix) Cynata Celyad Medi-post Anterogen Molmed Baxter Eleveflow Mesoblast Ltd. Micronit Microfluidics TAKARA BIO INC. Tigenix Capricor Therapeutics Astellas Pharma US, Inc. Pfizer Inc. STEMCELL Technologies Inc.

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Global Stem Cell Reconstructive Market- Industry Analysis and Forecast (2020-2027) - Good Night, Good Hockey

Cardiac Stem Cells Comments Off on Global Stem Cell Reconstructive Market- Industry Analysis and Forecast (2020-2027) – Good Night, Good Hockey | August 16th, 2020

Mystified by the need for defibrillation to save a 10-year-old from drowning, Michael Ackerman, M.D., Ph.D., vowed to dig for answers. That pivotal case during a Mayo Clinic pediatric cardiology residency was the catalyst for Dr. Ackermans career in genetic sleuthing of inherited sudden cardiac death syndromes. With help from the Center for Regenerative Medicine Biotrust, Dr. Ackermans team reprograms cell lines to zero in on precise causes and possible treatments for genetic heart disorders that increase the risk of sudden cardiac death. His research and practice focus on inherited conditions like long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT) and Brugada syndrome (BrS) along with heart muscle diseases such as hypertrophic cardiomyopathy (HCM).

Working with the Center for Regenerative Medicine has opened up a whole new investigative arm to our lab. It is bench to bedside research. We take cells from a blood sample from my patients and then reprogram those cells to become cardiac cells. This research effort has been a powerful tool in gene discovery to prove beyond a shadow of a doubt when a monogenetic variant is indeed the cause of a sudden cardiac death syndrome, says Dr. Ackerman.

Reprogramming cells to identify disease-causing mutations

Reprogramming a patients cells is like a step back in time to when the cells were initially forming in the mothers womb. At that time, cells were dividing and could become any type of cell or tissue in the body. Reprogrammed cells, known as induced pluripotent stem cells, can be redirected to become new heart cells. Dr. Ackermans team uses these patient-specific cell lines to create a disease in a dish model and investigate whether genetic mutations are causing the patients genetic heart disease such as long QT syndrome.

Once we think weve found the root cause of disease, we then go to the patients cell line. We ask, does it show in the dish, in that patients re-engineered heart cells, a prolonged QT cellular phenotype? If it does, then we edit out and correct that variant of interest and at the cellular level test whether the abnormality disappears, says Dr. Ackerman.

Dr. Ackermans team then introduces that genetic variant into normal, healthy cells. If those cells produce a long QT phenotype, they have proof that exact genetic variant is the cause.

Using this disease in a dish model and other genetic sleuthing strategies, Dr. Ackermans team has discovered six of the 17 known genes that cause long QT syndrome. And, they have recently described two entirely new syndromes. One is triadin knockout syndrome, a heart arrhythmia that could lead to cardiac arrest in children during exercise. The second is an autosomal recessive genetic mechanism for calcium release channel deficiency syndrome, prevalent within Amish communities. That key discovery solved the mystery of why so many Amish children were dying suddenly during ordinary childhood play. The disease in a dish model is also useful for discovering new therapies. After creating the patients disease in a dish, Dr. Ackermans team tests potential new drug compounds to see if they could be effective.

We are developing a new gene therapy for the most common genetic subtype of long QT syndrome.With this model, the gene therapy vector is essentially curing the diseased long QT phenotype in the dish, says Dr. Ackerman.

Almost quit research

Dr. Ackerman began medical and graduate school at Mayo Clinic in 1988, where he worked in a research lab next to then fellow trainee, Andre Terzic, M.D., Ph.D., who now is director of Mayo Clinic Center for Regenerative Medicine. Initially not seeing the relevance to patient care, Dr. Ackerman finished his Ph.D. and left research vowing to never, ever return. True to his mentors predictions that youll be back, Mike, Dr. Ackerman felt the pull back to research to address unmet medical needs of his patients.He joined Mayo Clinics faculty in 2000 as one of the first genetic cardiologists with a goal of establishing a practice for patients at risk of sudden cardiac death from genetic heart diseases. Dr. Ackerman now directs the Mayo Clinic Windland Smith Rice Genetic Heart Rhythm Clinic and the Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory.

Dr. Ackermans return to research has provided many answers for patients, with over 600 peer-reviewed publications that have occurred since that time 23 years ago when Dr. Ackerman and his team first solved that 10-year-old boys near fatal drowning. It was a mutation in the gene causing type 1 long QT syndrome.

Dr. Ackerman is one of the innovators the Center for Regenerative Medicine collaborates with as it seeks to be a global leader and trusted destination for regenerative care driven by research and education.

###

Tags: Brugada syndrome, Center for Regenerative Medicine Biotrust, hypertrophic cardiomyopathy, long Q T syndrome, Mayo Clinic Center for Regenerative Medicine, Michael Ackerman, People, Research, Stem cell research, sudden cardiac death

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Using stem cells to find causes and treatments to prevent ...

Cardiac Stem Cells Comments Off on Using stem cells to find causes and treatments to prevent … | August 15th, 2020

Global Stem Cell Therapy Market is expected to reach an approximate CAGR of 10.3% during the forecast period. The use of stem cell for treating medical conditions is referred to as stem cell therapy. Stem cells are undifferentiated cells and differentiate into specialized cell types.

This ability of stem cells to differentiate into cells of interest is used to treat diseases like diabetes, heart disease, hematopoietic disorders (for example leukemia, thalassemia, and others), degenerative disorders (osteoarthritis, Alzheimers disease, Parkinsons disease, chronic renal failure, congestive cardiac failure,) and others.

Some of the key players are Osiris Therapeutics, Inc. (US), MEDIPOST Co., Ltd. (South Korea), Anterogen Co., Ltd. (South Korea), Pharmicell Co., Ltd. (South Korea), Holostem Terapie Avanzate S.r.l. (Italy), JCR Pharmaceuticals Co., Ltd. (Japan), NuVasive, Inc. (US), RTI Surgical, Inc. (US), and AlloSource (US), Thermo Fisher Scientific are some of the key players operating in the global stem cell therapy market.

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Global Stem Cell Therapy Market, by Technique,

Global Stem Cell Therapy Market, by Product Type

Global Stem Cell Therapy Market, by Application

Global Stem Cell Therapy Market, by End-User

Geographically, Americas is the largest in the market owing to the increasing prevalence of heart diseases and growing healthcare expenditure. According to the Centers for Disease Control and Prevention in November 2017, report every year 735,000 Americans have a heart problem. Such a high number of heart patients in the Americas drives the market growth in this region.

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Europe (UK, Belgium, France, and Netherlands) is the second largest global stem cell therapy market during the forecast period. The increasing occurrence of stroke, cancer, and osteoarthritis drives the market in this region. According to Anthony Nolan organization 2017, annual review 1.4million people register for donating stem cell in 2017. Also, more than 2,200 searches for a lifesaving stem cell transplant were made in 2017 by UK people. Such a high demand for Stem cell transplantation in this region promotes the market.

Asia-Pacific was projected to be the fastest growing region for the global stem cell therapy market in 2017. The market is expected to witness growth owing to the rising prevalence of smoking in this region.

According to the American Cancer Society, Inc 2018, report China 48.9%, India 16.2%, Japan 11.2% accounts of cancer cases in this region. Such a high cancer rate in this region favors the stem cell therapy market in this region.

The Middle East and Africa accounts for the least share due to low per capita income and lack of availability of well-trained healthcare professionals. However, the rising oncology and technology both at the hospital level and in the community are expected to influence the market in a positive way.

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Key factors responsible for the market growth are the rising awareness for therapeutic application of stem cells in disease management, rising research for stem cell therapy applications, development of advanced genetic analysis techniques, increasing public-private investments for stem cell research, growing research in identification of new stem cell lines, and new developments in stem cell banking infrastructure are driving the growth of the global stem cell therapy market. Stem cells are used in the treatment of Alzheimers by replacing the diseased cells with stem cells

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Stem Cell Therapy Market Application Growth, Technology, Trends and Key Players Developments on Regional Industry Size Till 2023 - eRealty Express

Cardiac Stem Cells Comments Off on Stem Cell Therapy Market Application Growth, Technology, Trends and Key Players Developments on Regional Industry Size Till 2023 – eRealty Express | August 15th, 2020

Abstract

The emergence of several cell therapy candidates in the clinic is an encouraging sign for human diseases/disorders that currently have no effective treatment; however, scalable production of these cell therapies has become a bottleneck. To overcome this barrier, three-dimensional (3D) cell culture strategies have been considered for enhanced cell production. Here, we demonstrate a high-throughput 3D culture platform used to systematically screen 1200 culture conditions with varying doses, durations, dynamics, and combinations of signaling cues to derive oligodendrocyte progenitor cells and midbrain dopaminergic neurons from human pluripotent stem cells (hPSCs). Statistical models of the robust dataset reveal previously unidentified patterns about cell competence to Wnt, retinoic acid, and sonic hedgehog signals, and their interactions, which may offer insights into the combinatorial roles these signals play in human central nervous system development. These insights can be harnessed to optimize production of hPSC-derived cell replacement therapies for a range of neurological indications.

Stem cellsincluding adult and pluripotent subtypesoffer tremendous clinical promise for the treatment of a variety of degenerative diseases, as these cells have the capacity to self-renew indefinitely, mature into functional cell types, and thereby serve as a source of cell replacement therapies (CRTs). Human pluripotent stem cells (hPSCs) are of increasing interest for the development of CRTs due to their capacity to differentiate into all cell types in an adult, for which adult tissuespecific stem cells may, in some cases, not exist or may be difficult to isolate or propagate (1). For example, one potential CRT enabled by hPSCs is the treatment of spinal cord injury (SCI) with oligodendrocyte progenitor cells (OPCs). These hPSC-OPCs have recently advanced to a phase 2 clinical trial for the treatment of SCI (2) and are being considered for additional myelin-associated disorders in the central nervous system (CNS), including adrenoleukodystrophy, multiple sclerosis (3, 4), and radiation therapyinduced injury (5). In parallel, hPSC-derived midbrain dopaminergic (mDA) neurons are under consideration for Parkinsons disease therapy (6, 7).

The promise of hPSC-derived therapeutics such as hPSC-OPCs or mDA neurons motivates the development of manufacturing processes to accommodate the potential associated clinical need. For example, approximately 250,000 patients in the United States suffer from some form of SCI, with an estimated annual incidence of 15,000 new patients (8). Human clinical trials involving hPSC-OPCs have used dosages of 20 million cells per patient (9), such that the hypothetical demand would be over 1 trillion differentiated OPCs. It is therefore imperative to develop systems to enable discovery of efficient and scalable differentiation protocols for these therapies.

Differentiation protocols to direct hPSCs into functional OPCs (10, 11) have been developed to approximate the signaling environment at precise positions within the developing spinal cord. Positional identity of cells is guided patterning cues that form intersecting gradients along the dorsoventral axis, such as Sonic hedgehog (SHH), and rostrocaudal axis, such as retinoic acid (RA). In addition, certain cues are present along both axes, such as Wnts (1215). These signaling environments vary over time as the embryo develops (16, 17). However, translating this complex developmental biology to an in vitro culture requires optimization of a large combinatorial parameter space of signaling factor identities, doses, durations, dynamics, and combinations over many weeks to achieve efficient yield of the target cell type, and there remains open questions about the impact of cross-talk between patterning cues on the expression of cellular markers present in OPCs such as transcription factors Olig2 and Nkx2.2 (18). Strategies to derive OPCs and other potential CRTs from hPSCs have shown steady progress, especially with application of high-throughput screening technology (1921); however, current production systems for hPSC-derived CRTs involve two-dimensional (2D) culture formats that are challenging to scale (2228).

More recently, 3D culture systems have demonstrated strong potential for a larger scale and higher yield (29) of hPSC expansion and differentiation than 2D counterparts, as well as compatibility with good manufacturing practice (GMP) standards (3033). While high-throughput systems for screening 3D cell culture environments have been applied to basic biological studies of hPSC proliferation (34), we envision that this technology could additionally be applied toward systematically optimizing production strategies for CRTs to accelerate the pace of their discovery and development toward the clinic while simultaneously uncovering new interactions among signaling cues that affect cell fate. Here, we harness the powerful capabilities of a uniquely structured microculture platform (35, 36), to screen dosage, duration, dynamics, and combinations of several cellular signaling factors in 3D for hPSC differentiation (Fig. 1). The independent control of gel-encapsulated cells (on pillar chip) and media (in well chip) enables simultaneous media replenishment for more than 500 independent microcultures in a single chip. Furthermore, we use custom hPSC reporter cell lines (37) to enable live imaging of proliferation and differentiation of OPCs for over 80 days on the microculture chip. One thousand two hundred combinatorial culture conditions, amounting to 4800 independent samples, were screened while consuming less than 0.2% of the reagent volumes of a corresponding 96-well plate format. Furthermore, the robust dataset enabled statistical modeling to identify relative differentiation sensitivities to, and interactions between, various cell culture parameters in an unbiased manner. Last, we demonstrate the generalizability of the platform by applying it toward a screen for differentiation of tyrosine hydroxylaseexpressing dopaminergic neurons from hPSCs.

(A) A micropillar chip with cells suspended in a 3D hydrogel is stamped to a complementary microwell chip containing isolated media conditions to generate 532 independent microenvironments. One hundred nanoliters of hPSCs suspended in a hydrogel is automatically dispensed onto the micropillars, and 800 nl of media is automatically dispensed into the microwells by a robotic liquid handling robot programmed to dispense in custom patterns. The independent substrate for cells and media enables screens of combinations of soluble cues at various dosages and timings. Scale bar, 1 mm. (B) Timeline of exogenous signals for in vitro 3D OPC differentiation from hPSCs and anticipated cellular marker expression along various differentiation stages.

Initially, we assessed whether hPSCs could be dispensed in the microculture platform system uniformly and with high viability. Quantification of total, live, and dead cell counts across the microchip indicates uniform culture seeding and cell viability at the initiation of an experiment (fig. S1).

We then used a custom-made Nkx2.2-Cre H9 reporter line, which constitutively expresses DsRed protein but switches to green fluorescent protein (GFP) expression upon exposure to Cre recombinase, to longitudinally monitor proliferation and differentiation of hPSCs to Nkx2.2+ oligodendrocyte progenitors in 3D on the microchip platform. A small range of culture conditions from previously published protocols of OPC differentiation were selected for an initial, pilot differentiation experiment, and the GFP expression was quantified after 21 days of differentiation. Cell morphology changes accompanying neural lineage commitment and maturation were clearly observed at later stages in the 3D differentiation (movie S1 and fig. S2) as cultures were maintained and monitored for up to 80 days on the microchip. We then developed fluorescence image analysis pipelines for quantification of nuclear and cytoplasmic marker expression via immunocytochemistry for endpoint analyses at various times (fig. S3). Together, these results support the robust and long-term culture potential and cellular marker expression readout of this miniaturization methodology for hPSC differentiation screening.

hPSC seeding density. We first focused on parameters within the first week of 3D differentiation into OPCs (Fig. 2A). The importance of autocrine, paracrine, and juxtacrine signaling mechanisms among cells in many systems led us to anticipate that the density of cells at the start of differentiation could affect the early neural induction efficiency and, consequently, the efficiency of OPC differentiation. We therefore demonstrated the ability of this microculture platform to test a range of initial hPSC seeding densities on day 2 (fig. S1) and assessed the effect of seeding density on Olig2 expression. We observed notable differences in levels of cell-to-cell adhesion in hPSC cultures by day 0, 2 days after initial seeding (Fig. 2Bi). Then, after 15 days of differentiation, we observed a trend that lower hPSC seeding density, between 10 and 50 cells per pillar, increased OPC specification slightly (Fig. 2Bii).

(A) Timeline of key parameters in the early phase of OPC differentiation. (B) i. Bright-field images of 3D H9 microculture sites at day 0 seeded with varying cell densities and the immunocytochemistry images of Olig2 (red) expression at day 15. Scale bar, 100 microns. ii. Quantification of day 15 Olig2 expression with respect to seeding density and SAG dose. *P value < 0.05 using Tukeys Method for multiple comparisons. (C) i. Montage of 360 fluorescence confocal images representing 90 unique differentiation timelines on a single microchip stained for Hoechst (blue) and Olig2 (red) after 21 days of differentiation. ii. Trends in Olig2 expression at days 15 and 21 in various CHIR and RA concentrations and durations (short CHIR, days 0 to 1; long CHIR, days 0 to 3). Error bars represent 95% confidence intervals from four technical replicates.

Timing of SMAD inhibition relative to RA and Wnt signals. The formation of the neural tube in human development (12) results from cells in the epiblast being exposed to precisely timed developmental signals such as Wnt (38) and RA that then instruct neural subtype specification (39). This led us to hypothesize that the overall differentiation efficiency of hPSCs to OPCs in this 3D context in vitro would be sensitive to the timing at which RA and Wnt signals were introduced during neural induction. Therefore, we induced neuroectodermal differentiation of hPSCs via inhibition of bone morphogenetic protein (BMP) signaling using the dual SMAD inhibition approach (40), with LDN193189 (hereafter referred to as LDN) and SB431542 (hereafter referred to as SB), and tested a range of times (0, 2, and 4 days) at which RA and Wnt signals (by CHIR99021, hereafter referred to as CHIR) were introduced into the culture. We observed a strong correlation between early addition of RA/CHIR and OPC specification such that combined exposure of RA and CHIR signals with SMAD inhibition on day 0 resulted in up to sixfold higher Olig2 expression in some cases (fig. S4), potentially implicating an important role of synchronized exposure of RA and CHIR signals with SMAD inhibition for specifying Olig2+ progenitors. For subsequent experiments, we kept the timing of RA and CHIR addition at day 0 and evaluated how the dose and duration of these signals may affect Olig2+ specification.

Dose and duration of key signaling agonists. We examined the combinatorial and temporal effects of three signaling cues that form gradients across intersecting developmental axes in the neural tube to influence specification of oligodendrocyte progenitors: RA (present along the rostrocaudal axis of the CNS development), SHH (41) (a morphogen that patterns the dorsoventral axis of the developing CNS and is activated by smoothened agonist, hereafter referred to as SAG), and Wnt (present along both the rostrocaudal and dorsoventral axes). Because OPC specification is likely sensitive to the relative concentrations of these cues, for example, given the importance of morphogen gradients in oligodendrocyte differentiation in the developing neural tube (12), we assessed the Olig2 expression resulting from a full factorial combinatorial screen of these cues (fig. S5). Most notably, we observed positive correlations in Olig2 expression in response to increasing RA dose and increasing duration of CHIR exposure from days 0 to 4 of differentiation (Fig. 2C). Without CHIR, an increase in RA from 10 to 1000 nM resulted in a 10-fold increase of Olig2 expression by day 21. A similar 10-fold increase in Olig2 expression was observed at an RA concentration of 100 nM if CHIR was present for the first 3 days of differentiation (Fig. 2C). Analysis of variance (ANOVA) analysis revealed a strong effect size for RA when added early in the differentiation, as well as an interaction between RA dose and longer CHIR duration, in specifying Olig2+ cells in this 3D context (fig. S5), consistent with previous work conducted in 2D in vitro formats (19, 42).

In other developmental systems, the activity of the Wnt signaling pathway was observed to be biphasic (43), whereby activation of the pathway initially enhances cardiac development but later represses it. As this complex signaling profile has been applied to enhance cardiomyocyte differentiation protocols in vitro (44), we analogously investigated whether adding antagonists of key signaling pathways after pathway activation could further enhance the OPC differentiation efficiency by adjusting the dorsoventral and rostrocaudal positioning in vitro. Maintaining the 5 M CHIR for days 0 to 3 from the previous experiment, we used IWP-2 (an inhibitor of the Wnt pathway), GANTT61 (an antagonist of SHH signaling), and DAPT (a Notch pathway antagonist) (Fig. 3A) to inhibit endogenous autocrine/paracrine and/or basal signaling. We used a full factorial analysis of these cues to additionally probe for combinatorial interactions among the pathway inhibitors.

(A) Timing of addition for three inhibitory signaling cuesGANTT61, IWP-2, and DAPTin the OPC differentiation protocol. (B) i. Olig2+, Nkx2.2+, and the proportion of total Olig2+ that are Nkx2.2+/Olig2+ cells in at day 21 in response to full factorial combinations of selected novel signaling antagonists. ii. Immunocytochemistry images of costained Olig2 (red) and Nkx2.2 (green) cells. Scale bar, 100 m. Error bars represent 95% confidence intervals from four technical replicates.

To further refine the markers for OPC specification, we measured Nkx2.2 expression in addition to Olig2 and quantified the proportion of cells coexpressing both OPC markers. Most notably, a significant decrease in %Olig2 was observed in response to Notch inhibitor DAPT across all conditions tested (Fig. 3Bi). The same trend was not observed with respect to %Nkx2.2. This result could point to a role for Notch signaling in maintaining or promoting specification of Olig2+ progenitorsa hypothesis not previously examined to our knowledgeand serves as preliminary evidence to test Notch agonists such as DLL-4 in follow-up studies of OPC optimization. This effect may be mediated by an interaction with the SHH pathway (45).

A slight increase in %Olig2+ cells was detected with increasing Wnt inhibitor IWP-2 dose when no SHH inhibitor GANTT61 was present, as was a slight increase in %Nkx2.2+ cells as a function of increasing IWP-2 and GANTT61 dose, pointing to a potential interaction between these two cues in inducing Nkx2.2 expression. The highest proportion of Olig2+Nkx2.2+ cells was observed at the highest IWP-2 and GANTT61 doses and was not influenced by DAPT exposure (Fig. 3Bii). As CHIR was present between days 0 and 3 in the differentiation, it seems that the role of Wnt signaling changes during the 21-day differentiation window of hPSCs to OPCs in that initially (days 0 to 3) it promotes OPC differentiation but shifts to an inhibitory role at later stages (days 4 to 21). To examine the extent of reproducibility of these findings, we tested the effect of temporal modulation of Wnt signals in a human induced pluripotent stem cell (hiPSC) line, TCTF, and found that the general trend of activation followed by inactivation of Wnt signaling would increase the proportion of Olig2+ cells at day 21 (fig. S6).

Although the levels of key signaling cues may vary temporally within the natural developmental environment of certain target cell types, such as within the neural tube where a dynamic SHH gradient along the dorsoventral axis patterns pMN development (16, 17), the dosage of signaling cues in the media for in vitro stem cell differentiation protocols is often applied at a constant level throughout the culture period. On the basis of this discrepancy, we applied the micropillar/microwell chip to screen through numerous temporal profiles of SAG, as well as RA due to its analogous role along the rostrocaudal axis during spinal cord development, by dividing the signal window into early and late stages that were dosed independently to form constant, increasing, and decreasing dose profiles over time (Fig. 4A). To gain additional insights into OPC marker expression, we measured Tuj1 expression and calculated the proportion of Olig2+ cells that coexpressed Tuj1 to potentially identify any modulators of the balance between Olig2+ cells that proceed down a motor neuron fate (which are both Olig2+ and Tuj1+) versus an oligodendrocyte fate (Olig2+/Nkx2.2+).

(A) Timeline of early and late windows for RA and SAG exposure. (B) i. Hierarchical cluster analysis of standardized (z score) phenotypic responses to temporal changes in RA and SAG dose during OPC differentiation. ii. Representative immunocytochemistry images of each major category of endpoint population phenotype mix of Olig2 (red), Nkx2.2 (green), and Tuj1 (orange) expression. Scale bar, 100 m. iii. Olig2, Nkx2.2, and coexpression of Olig2+Nkx2.2+ and Olig2+Tuj1+ at day 15 in response to time-varying doses of SAG. Error bars represent 95% confidence intervals from four technical replicates. *P value < 0.05.

To consider all measured phenotypes simultaneously, we applied a hierarchical cluster analysis from which we were able to identify several patterns. A broad range of endpoint phenotype proportions of Olig2, Nkx2.2, and Tuj1 was found to result from varying the temporal dosing of only two signaling cues, RA and SAG, pointing to a very fine sensitivity to temporal changes in signal exposure in these populations. Four categories of the endpoint marker expression profiles were created to further interpret the cluster analysis. Categories 1 and 2 are composed of phenotypes ranking low on OPC progenitor fate (low Olig2 and/or Nkx2.2 expression), all of which shared the low dosing of RA at 0.1 M between days 2 and 21 of the differentiation, further emphasizing the strong impact of RA on OPC yield. In contrast, category 3composed of the highest Olig2 and Nkx2.2 expression as well as Olig2+Nkx2.2+ proportioncorrelated with the highest dose of early SAG but had negligible differences across doses of late SAG (Fig. 4Biii, and fig. S7). Last, category 4 points to a biphasic relationship of Nkx2.2 expression as a function of RA dosage, where a high dose of RA of 1 M in the late stage of differentiation resulted in lower Nkx2.2 expression (fig. S8) compared with a consistent RA of 0.5 M throughout the entire differentiation. It appears that Olig2 and Nkx2.2 undergo maxima under different RA dosage profiles (fig. S8), and therefore, the use of coexpressing Olig2+Nkx2.2+ cells as the main metric when optimizing OPC differentiation may be most suitable.

We sought a comprehensive, yet concise, analysis to describe individual and combinatorial effects of all 12 culture parameters (e.g., signal agonist and antagonist dosages and timings) on the results of the more than 1000 unique differentiation conditions involved in this study. To this end, we fit generalized linear models to correlate the expression and coexpression of Olig2, Nxk2.2, and Tuj1 to individual input parameters within the 12 culture parameters involved in this study, and the 132 pairwise interactions between them. First, we identified significant parameters of interest for each phenotype measured using a factorial ANOVA (fig. S9). After applying a Benjamini and Hochberg false discovery rate correction for multiple comparisons (46), we fit an ordinary least squares model of the statistically significant terms to the phenotype of interest. The parameter coefficients were analyzed as a measure of relative influence on the expression of a certain endpoint phenotype, such as Olig2+Nkx2.2+ cells, and could be interpreted as a sensitivity analysis of key parameters on the OPC specification process. The most significant parameters were then sorted by their effect magnitude (Fig. 5B).

(A) Identification of statistically significant culture parameters using a factorial ANOVA of all single and pairwise effects on Nkx2.2 expression subject to the Benjamini and Hochberg false discovery rate (B&H FDR) correction. (B) Effect magnitude of significant culture parameters for i. Nkx2.2 expression, ii. Olig2 expression, iii. and coexpression of Olig2 and Nkx2.2. (C) i. Diagram summarizing results and effect magnitude of significant culture parameters for Olig2 and Nkx2.2 coexpression within the Olig2+ population and ii. effect magnitude of significant culture parameters for Olig2 and Tuj1 coexpression within the Olig2+ population.

RA, a rostrocaudal patterning cue, was among the most impactful parameters in this study for Olig2 and Nkx2.2 expression (Fig. 5Bi and ii). In particular, a high RA dose (1 M) early in the differentiation (days 0 and 1) emerged as the most influential culture parameter in the acquisition of OPC fate (coexpression of Olig2 and Nkx2.2) (Fig. 5Bi to iii). In addition, the dose of SAG from days 4 to 10 of differentiation exerted a markedly more significant impact on OPC fate induction than from days 10 to 21 of differentiation, in line with the previous analysis (Fig. 4). IWP-2 and GANT were observed to correlate positively with coexpression of Olig2 and Nkx2.2 as well. Furthermore, this analysis identified two cases of culture parameters interacting in a synergistic manner to promote OPC differentiation. First, higher doses of RA during days 0 to 2 followed by SAG during days 4 to 10 were found to promote higher Nkx2.2 expression. In addition, longer CHIR duration (from days 0 to 4) along with higher GANT dose promoted coexpression of Nkx2.2 and Olig2.

We created a new differentiation protocol from the parameters isolated in this screen to have the most influence in specifying Olig2+Nkx2.2+ progenitors (Fig. 5Biii) and carried out the differentiation into the later stages of OPC maturation in a larger-scale format to assess the ability of this optimized protocol to create mature oligodendrocytes. The protocol was able to produce platelet-derived growth factor receptor (PDGFR)expressing cells by day 60 across multiple hPSC lines, as well as O4-expressing cells by day 75 and myelin basic protein (MBP) expressing cells and myelination ability at day 100 (fig. S10).

The OPC screening identified new conditions that affect cell differentiation, and we then sought to demonstrate the generalizability of this approach by conducting a different study. Specifically, we screened 90 unique hPSC differentiation protocols for tyrosine hydroxylase+ mDA neurons (Fig. 6). Exposure of CHIR was divided into three periods (early, middle, and late), and dosage for each period was varied independently. This screening strategy uncovered a key window of CHIR competence between days 3 and 7 (early), a negligible effect of CHIR between days 8 and 11 (middle), and an inhibitory effect of CHIR between days 12 and 25 (late) of mDA differentiation. These data further illustrate the existence of biphasic signaling activity during the differentiation process and underscore the need to improve the temporal dosing of several signaling agonists across a range of hPSC-derived CRTs.

(A) Timeline of small-molecule addition for differentiation of mDA neurons from hPSCs. (B) Montage of 90 unique differentiation timeline to test temporal profiles of CHIR dose stained for tyrosine hydroxylase (TH) and Tuj1. Scale bar, 1 mm. (C) Immunocytochemistry images of i. low, ii. medium, and ii. high proportions of TH+ (yellow) neurons (red) dependent on the temporal profile of CHIR exposure. Scale bar, 100 m.

The clinical emergence of several cell-based therapy candidates (47) is encouraging for human diseases/disorders that currently have no effective small molecule or biologic-based therapy. As research and development into CRT candidates continues to progress, cell production has emerged as a bottleneckas delivery vectors recently have in gene therapyand improved tools will be necessary to enable higher quality and yield in cell manufacturing. Although previous studies have reported ~90% hPSC differentiation efficiency into Olig2+ progenitors using 2D culture formats (19), the 2D culture format constrains the space in which cells can expand to the surface area of the culture plate that limits the overall cell yield that can be produced. The adoption of scalable 3D culture formats, which have demonstrated the ability to produce up to fivefold higher quantities of cells per culture volume, shows promise in surpassing limits of 2D cell expansion (2933) and could result in a higher overall production quantity of target cells even if differentiation efficiencies were lower than what has been reported in 2D. Therefore, the 3D screening and analysis strategy presented here is relevant for numerous emerging CRT candidates for which conversion of a stem or progenitor cell, such as a hPSCs (48), to a therapeutically relevant cell type requires searching through a large in vitro design space of doses, durations, dynamics, and combinations of signaling cues over several weeks of culture.

Notably, to emulate a ubiquitous and naturally occurring phenomenon in organismal development (16, 49), we dynamically varied key signaling cues in our screening strategy, tuning dosage over time. These analyses revealed new biological insights into the dynamic process by which cell competence to signals and fate are progressively specified (50). For example, by applying this platform to screen through several dynamic signaling levels simultaneously, we observed that the differentiation toward Nkx2.2+ progenitors is very sensitive to the dose of RA between days 0 and 1 and the dose of SAG between days 4 and 10. After these respective time windows, the effect of each respective signal in producing Nkx2.2+ progenitors is decreased, potentially pointing to a decrease in cellular competence to each of these signals over the course of OPC development. These cases of stage-specific responses to signaling cues, revealed by our screening platform, create a new dimension for future optimization of cell production.

To effectively navigate this enormous parameter space across doses, durations, dynamics, and combinations of signaling cues and resulting differentiation outcomes, we developed a robust sensitivity analysis strategy that can rank effect sizes to reveal which parameters should be the focus of optimization to modulate expression of target markers of interest (49) and, by contrast, which parameters exert minimal impact and can thus be neglected. For example, titration of RA dose will exert a significantly higher impact on differentiation efficiency than several other culture parameters combined. Furthermore, insights from this study could reduce the necessary quantity of SHH agonist by more than 50% to achieve similar levels of OPC differentiation. As these cell production processes translate from bench scale to industrial scale, awareness of key parameters that influence critical quality attributes (18) of the cell therapy product (such as expression of specific cellular markers) will be a necessary step in reliably producing these therapeutic cell types at scale for the clinic (51).

The wealth of combinatorial and temporal signaling patterns identified in this study can be analyzed in the context of CNS development as well. We observed a potential case of biphasic activity for the Wnt signaling pathway as both activation and inhibition appeared to increase expression of OPC markers Nkx2.2 and Olig2. In particular, this effect was seen with initial Wnt activation by CHIR during days 0 to 3 of OPC differentiation followed by inhibition by IWP-2 during days 4 to 21 of OPC differentiation. The Wnt pathway has shown stage-specific activity in cardiac and hematopoietic development (43, 44), which may thus be a conserved feature across several developmental systems. Wnt signals play an important role in the gastrulation of the embryo to form the primitive streak (38), yet in the subsequent stages of spinal cord development, Wnt signals induce a dorsalizing effect (52), whereas oligodendrocytes originate from the motor neuron domain on the ventral side. Therefore, suppressing endogenous Wnt signals in vitro after initial activation of Wnt may better recapitulate the natural developmental signaling environment of developing oligodendrocytes. Alternatively, as Wnt signals also play a role in rostrocaudal patterning of the CNS, these insights may further point toward a rostrocaudal region of the CNS during this developmental window that is optimal to recapitulate in vitro for OPC production. The oligodendrocytes created through this protocol, which expressed OTX2 at day 10 (fig. S2C), may resemble OPCs in the midbrain/hindbrain region. It is conceivable that exposure to the Wnt antagonist, IWP-2, induced a position rostral to the spinal cord during the differentiation window. This biphasic Wnt trend was seen again in our analysis of differentiation of mDA neurons, underscoring that stage-specific responses may be a conserved feature across several differentiation processes aiming to recapitulate a precise cellular position across several axes of patterning signals during natural development.

Furthermore, the statistical model identified an interaction between RA and SAG (an SHH agonist) in the early differentiation windows for specifying Nkx2.2+ progenitors (Fig. 5B), which has not been previously reported to our knowledge. In the developing CNS, RA signaling influences rostrocaudal positional identity, whereas SHH signaling specifies dorsoventral positional identity. Therefore, this statistical interaction found in the screen may represent intracellular cross-talk between the RA and SHH signaling pathways to integrate both patterning dimensions into Nkx2.2+ progenitor identity. This finding builds on what is known about RA and SHH signals for Olig2+ progenitor development in the spinal cord (53, 54).

Additionally, the 3D context of this screening platform enables high-throughput investigation into neurodevelopmental model systems that can offer unique perspectives beyond what is capable in 2D screening platforms, for example, by recapitulating cell-to-cell interactions, cytoskeletal arrangement, and multicellular patterning in 3D. The lumen structures that were observed during the neural induction period (fig. S2B and movie S1) in response to caudalizing conditions (high Wnt and RA) could be the basis of future organoid screening strategies to probe early multicellular arrangement and the effect of lumen size and shape on cell fate determination at various positions along the rostrocaudal and dorsoventral axes.

In conclusion, we demonstrate the versatile capabilities of a unique microculture platform for 3D differentiation screening and optimization of hPSC-derived cell therapies, whereby 1200 unique OPC differentiation timelines, and a total of over 4800 independent samples, were investigated using 0.2% of the reagent volumes required in a standard 96-well plate format. The dense dataset enabled subsequent statistical modeling for empirical optimization of the differentiation process and identified differential sensitivities to various culture parameters across time. These insights are important in developing strong process knowledge for manufacturing stem cell therapeutics as they continue to emerge in the clinic, and therefore, such screening strategies may accelerate the pace of discovery and development. Simultaneously, this combinatorial 3D hPSC differentiation screens may provide new insights on the basic biology of human development.

Human embryonic stem cells (H9s: National Institutes of Health Stem Cell Registry no. 0062) and hiPSCs (TCTFs: 8FLVY6C2, a gift from S. Li) were subcultured in monolayer format on a layer of 1% Matrigel and maintained in Essential 8 medium during expansion. At 80% confluency, H9s were passaged using Versene solution and replated at a 1:8 split.

H9s were dissociated into single cells using Accutase solution and resuspended in Essential 8 medium containing 10 M Y-27632 (ROCK Inhibitor). H9s were counted and resuspended at defined densities in 50% Matrigel solution on ice. While chilled, 100 nl of H9s in 50% Matrigel solution was deposited onto the micropillars at a density of 100 cells per pillar, unless otherwise noted, using a custom robotic liquid handling program and then incubated at 37C for 20 min to promote gelation of 3D cultures. The micropillar chip was then inverted and placed into a fresh microwell chip containing cell culture media (table S1). All liquid dispensing into the microculture platform was performed with a DIGILAB OmniGrid Micro liquid handler with customized programs for deposition patterns. Between days 2 and 0, cells were kept in E8 media supplemented with 10 M ROCK Inhibitor. Between days 0 and 10, cells were kept in differentiation media made of a base of 50% Dulbeccos Modified Eagles MediumF12, 50% Neurobasal, 0.5% penicillin/streptomycin (pen/strep), 1:100 GlutaMAX supplement, 1:50 B27 supplement, and 1:50 N2 supplement. Between days 10 and 21, cells were kept in differentiation media made of a base of 100% Neurobasal, 0.5% pen/strep, 1:100 GlutaMAX supplement, 1:50 B27 supplement, and 1:50 N2 supplement. After day 21, OPCs were transitioned to maturation media consisting of 100% Neurobasal, 0.5% pen/strep, 1:100 GlutaMAX supplement, 1:50 B27 supplement, 1:50 N2 supplement, insulin-like growth factor 1 (10 ng/ml), platelet-derived growth factor (PDGF)AA (10 ng/ml), NT-3 (10 ng/ml), and insulin (25 g/ml). Media were changed daily by transferring the micropillar chip into a microwell chip containing fresh media every other day using a custom-made mechanical Chip Swapper for consistent transfer. Technical replicates included two different dispensing patterns to average out positional effects across the microchip.

At the endpoint of the experiment, the micropillar chip was carefully removed from the microwell chip and placed in new microwell chip containing calcein AM, ethidium homodimer, and Hoechst diluted in sterile phosphate-buffered saline (PBS) (dilution details in table S1). The micropillar chip was incubated for 20 min and then transferred to a new microwell chip containing PBS, and individual microenvironments were imaged using fluorescence microscopy.

At the endpoint of the experiment, the micropillar chip was carefully removed from the wellchip and placed into a bath of 4% paraformaldehyde for 15 min to fix cell cultures. Then, the micropillar chip was washed twice in PBS for 5 min each and placed into a bath of 0.25% Triton X-100 + 5% donkey serum in PBS for 10 min to permeabilize cells. After permeabilization, the micropillar chip was washed five times in 5% donkey serum for 5 min each, transferred to a wellchip containing primary antibodies of interest diluted in PBS + donkey serum (dilution details in table S1), and stored overnight at 4C. After primary staining, the micropillar chip was washed twice in PBS for 5 min each, placed into a microwell chip containing the corresponding secondary antibodies (dilution details in table S1), and incubated at 37C for 2 hours. After secondary staining, the micropillar chip was washed twice in PBS for 5 min each and placed into a wellchip containing PBS; individual microenvironments were imaged using fluorescence confocal microscopy.

Stained micropillar chips were sealed with a polypropylene film (GeneMate T-2452-1) and imaged with a 20 objective using a Perkin Elmer Opera Phenix automated confocal fluorescence microscope available in the High-Throughput Screening Facility at University of California, Berkeley. Laser exposure time and power were kept constant for a fluorescence channel within an imaging set. Images were scored for marker expression depending on nuclear or cytoplasmic localization (fig. S3).

Fixed cultures on micropillars at day 15 were stained with 4,6-diamidino-2-phenylindole (DAPI) and imaged using an upright Olympus BX51WI microscope (Olympus Corporation) equipped with swept field confocal technology (Bruker) and a Ti:sapphire two-photon Chameleon Ultra II laser (Coherent) was used. The two-photon laser was set to 405 nm, and images were captured using an electron multiplying charge-coupled device camera (Photometrics). Prairie View Software (v. 5.3 U3, Bruker) was used to acquire images, and ImageJ software was used to create a video of the z-series.

Quantified image data were then imported into Python for statistical data analysis (55) and visualization. For comparisons between datasets acquired across different experimental sessions, raw data were scaled and centered by z score, and descriptive statistics were calculated from four technical replicates. Error bars represent 95% confidence intervals, unless otherwise specified. For the hierarchical cluster model, the Euclidean distance was used to measure pairwise distance between each observation, and the unweighted pair group method with arithmetic mean (UPGMA) algorithm was used to calculate the linkage pattern. A Benjamini and Hochberg false discovery rate correction was applied as needed to correct for multiple comparisons. Code is available upon request.

Acknowledgments: We thank M. West of the High-Throughput Screening Facility (HTSF) at UC Berkeley and E. Granlund of the College of Chemistry machine shop for machining custom parts. In addition, we are grateful to G. Rodrigues, M. Adil, and J. Zimmermann for participating in the discussions on the work. Funding: This research was supported by the California Institute for Regenerative Medicine (DISC-08982) and the NIH (R01-ES020903) and Instrumentation Grant (S10OD021828) that provided the Perkin Elmer Opera Phenix microscope. R.M. was supported in part by an NSF Graduate Research Fellowship. Author contributions: R.M., D.S.C., and D.V.S. conceived various parts of the project and supervised the study. R.M. designed the experiments and managed the project workflows. X.B. created Nkx2.2-Cre H9 reporter lines. R.M., E.T., and E.C. performed the experiments. R.M. conducted statistical modeling, and A.M. aided in statistical testing. R.M., D.S.C., and D.V.S. analyzed and interpreted the data. R.M. wrote the manuscript with revisions from J.S.D., D.S.C., and D.V.S. Competing interests: R.M., D.S.C., and D.V.S. are inventors on a U.S. patent pending related to this work filed by the University of California, Berkeley (PCT/US2020/029553, filed on 23 April 2020). D.V.S. is the inventor on two U.S. patent pendings related to this work filed by the University of California, Berkeley (PCT/US2016/055362, filed on 4 October 2016; no. PCT/US2016/055361, filed on 5 October 2015). All other authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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High-throughput 3D screening for differentiation of hPSC-derived cell therapy candidates - Science Advances

Cardiac Stem Cells Comments Off on High-throughput 3D screening for differentiation of hPSC-derived cell therapy candidates – Science Advances | August 10th, 2020

Dyne Therapeutics started out last April with a modest $50 million to mine targeted muscle disease therapies from its in-house conjugate technology. The biotech has now convinced more investors that its got gems on its hands, closing $115 million in fresh financing to push its next-gen oligonucleotide drugs into the clinic.

Vida Ventures and Surveyor Capital led the round, joined by a group of other new backers including Wellington Management Company, Logos Capital and Franklin Templeton.

Atlas where Dyne was incubated also returned alongside Forbion and MPM.

Stefan Vitorovic, who co-founded Vida with Arie Belldegrun and others, took the lead on this one. Dynes FORCE platform matches exactly their appetite for bold visions in the future of medicine, with the potential to deliver life-changing outcomes for patients with muscle diseases, he said.

This is how the biotech plans to do it: By linking an antibody to an oligonucleotide, Dynes therapies are engineered to hone in on muscle cells and degrade only disease-causing RNA, thereby avoiding systemic toxicity issues.

Romesh Subramanian, a co-founder of what is now Translate Bio, helped launch the operations as an entrepreneur-in-residence at Atlas. Hes since handed the CEO baton to Joshua Brumm and moved to the CSO post.

When you deliver a naked oligo, very little gets to the muscle, he told C&EN back in 2019.

That means a lack of specificity and potential safety problems for drugs like Sareptas controversial Exondys 51. While Dyne is aiming directly at that market with its Duchenne muscular dystrophy program, its initial focus is on myotonic dystrophy.

Trailing closely is a third therapy for facioscapulohumeral muscular dystrophy, followed by discovery work in the cardiac and metabolic arenas.

How would the approach compare to gene therapies, which are cropping up at Sarepta and other newer players focused on muscle diseases? We didnt get a chance to ask Dyne, which is shying away from interviews this morning perhaps a sign of upcoming plans in a booming biotech IPO market.

Under Braum, Dyne has been on a bit of a hiring spree recently, poaching Susanna High from bluebird to be COO, appointing ex-Celgene exec Daniel Wilson as VP of intellectual property, and scooping Debra Feldman from Sage Therapeutics as head of regulatory.

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Vida Ventures co-leads Dyne's $115M megaround for next-gen oligo therapies aimed squarely at muscles - Endpoints News

Cardiac Stem Cells Comments Off on Vida Ventures co-leads Dyne’s $115M megaround for next-gen oligo therapies aimed squarely at muscles – Endpoints News | August 10th, 2020

Adam Smith (1723-1790) was not who you think he was. I'm talking about the original Adam Smith who wrote The Wealth of Nations (1776) and spent most of his life in Edinburgh, Scotland. The more recent "Adam Smith" - nom de plume of the late George Goodman who wrote The Money Game (1967) - bears much more resemblance to the Adam Smith you think you know.

The first Adam Smith would have had little interest in stock market wisdom because he regarded himself as a moral philosopher rather than an analyst of markets. In fact, he was not even a capitalist. His works do not include the words "capitalist" or "capitalism" because neither came into use in his lifetime. The first mention of "capitalism" in print was in the 1854 novel The Newcomes by William Makepeace Thackeray, whose father had been involved with the East India Company. Karl Marx, oddly enough, helped popularize the term in his classic Das Kapital (1867). The irony is that if Marx did not quite invent the concept of capitalism, he certainly made the term popular in the process of opposing and bashing it.

No one can know what Adam Smith would have thought about free market capitalism as presently practiced, nor can we guess what he would have thought about the aftermarket in shares which we call "the stock market." The first stock exchanges came into being a couple of years after his death and shares were traded in only a small handful of companies including the still extant Bank of New York (NYSE:BK). Security trading over Smith's lifetime was concerned primarily with credit instruments, the exceptions being one-off exchanges organized by and for the British and Dutch East India Companies. So no capitalism, no market opinions from Adam Smith. Sorry to have to tell you.

The primary interest of Adam Smith was the goal which gave his book its full title - an inquiry into the nature and causes of the wealth of nations, in short, the well-being of the general populace. Counterintuitively paired with this was the self-interest which led tradesmen and the early industrialists to seek profit. He used the term "invisible hand" only three times in his writing and just once in The Wealth of Nations, to wit:

The rich consume little more than the poor, and in spite of their natural selfishness and rapacity, though they mean only their own conveniency, though the sole end which they propose from the labours of all the thousands whom they employ be the gratification of their own vain and insatiable desires, they divide with the poor the produce of all their improvements. They are led by an invisible hand to make nearly the same distribution of the necessaries of life which would have been made, had the earth been divided into equal portions among all its inhabitants, and thus without intending it, without knowing it, advance the interest of the society, and afford means to the multiplication of the species...the beggar, who suns himself by the side of the highway, possesses that security which kings are fighting for."

This is the central core of Adam Smith's thinking. It has always interested me that the ultimate goals of Adam Smith and Karl Marx did not differ greatly. The important difference is that Smith believed in freedom of the market while Marx believed that the solution was the top-down mandate of a command economy. We are familiar at this point with the general course of events in top down economies. The 20th Century resolved that question definitively in favor of Smith's view, which we now call capitalism.

Smith, however, never imagined a world with an after-market of securities measured by such things as price earnings ratios and discounted free cash flow. He would have been astonished at the use of these and other forms of analysis central to modern markets including shares of corporations with thousands of shareholders and many millions of shares. The few larger businesses in his day - a few early industrialists and the enormous East India Companies - did not lend themselves to that kind of analysis.

Does that mean that the thinking of Adam Smith is useless in trying to understand value in the modern financial markets? Not at all. Smith's model of the invisible hand contains a clue as to the way he might have valued companies and their shares. In fact, the view of Adam Smith may take us back to the primary purpose of capital markets which focus on start-ups, IPOs, unicorns, perhaps even SPACs, and all companies in their early stages. Such companies seek capital with which they aspire to bring innovations. They hope to profit by serving the unmet and often unrecognized needs of a body of potential customers.

What Smith saw was the intricate interplay between the needs and desires of customers and the self-interest of a risk-taking capitalist. That is the core transaction of the capitalist system. Without so much as a glance at discounted future cash flow, Smith implicitly understood that for a business the important thing was the population for which a business might add value. The issues for the entrepreneur involve the accuracy of their estimate of that market, the share of that market they might expect to win, the revenues they might expect to receive, and the profit margin they might expect to realize on those revenues.

In short, Adam Smith's thinking may not ordinarily be very helpful in the after-market we call "the stock market" but is central to the universe of young and innovative companies. It is directly connected with the way businesses and customers are conjoined. What a business does for its customers, he implies, provides an outline of its ultimate value. For this reason, I see the conjunction of businesses and customers as potentially useful in thinking about leading companies in the current market, especially for those companies which cannot be analyzed usefully by the standard market metrics of sales, margins, earnings, PE, and discounted cash flow.

In Adam Smith terms, a company should be worth a reasonable return for what it contributes to the greater good of the general populace. This single sentence is at the heart of what I am calling the "Adam Smith Model" of valuation. Does it actually work when trying to value innovative companies? Can one make decisions based on this model? To a large degree I think it is the only really helpful approach in valuing companies driven by new products and concepts.

To show how this sort of analysis might work, I will start with my daughter's portfolio of innovative biotech companies, which she put together in the early days of the pandemic. It is a pretty good model of the kind of thing I have always kept a careful distance from. Her surprising success with this portfolio prompted my own internal debate.

My daughter is a bright young woman who will soon turn 50. She has a doctorate in art history from Penn but retrained as a nurse in order to live in the woods in western Massachusetts and raise her children as a single mom close to nature and away from urban centers. Her life is modeled more on Thoreau's Walden than on Ben Graham's The Intelligent Investor. Despite sitting at my dinner table for seventeen years she remained almost entirely ignorant about financial markets until recently. The after-market in stocks seemed to her insufficiently serious to deserve her attention, which might well have been Adam Smith's view had he lived to see it. I confess to having had similar thoughts myself at times but have suppressed them.

In recent years, however, prompted by the realization that she may one day retire and need an income, she has begun to take an interest in markets. Around the beginning of the COVID-19 crisis (on which she had early insight and much sound advice), she put together without telling me a portfolio of biotech companies. She did this on a very small scale. Over four or five months she is up well over 200%, an amount I have never made in anything like that period. Here's an excerpt from an email she sent me on her portfolio:

Yes, that's why I like leronlimab - CytoDyn (OTCQB:CYDY). It has many uses, a high safety profile (I don't give a second glance to drugs with a low safety profile-anyone could have seen that with hydroxychloroquine, and now dexamethasone-which is a broad-target immunosuppressant, hence will never be a commonly used drug for Covid). Leronlimab has a great safety profile and works with a known mechanism vs. the cytokine storm. Anything good for Covid (or the other viruses that are still around: SARS, MERS and Ebola) must not suppress the immune system as a whole (as do all steroids such as dexamethasone). Leronlimab is targeted at the CCR5 receptor-which makes it effective for coronaviruses as well as cancers and autoimmune disease. Amazing for metastatic cancer, including prostate (though the recent studies are on a hard to treat breast cancer), and probably other untreatable but common cancers. It's going to be great for HIV. It's going to work for host vs graft disease (post-transplants, when we go back to doing them). It also appears to work for NASH (non-alchoholic fatty liver disease, which has increased dramatically in numbers, but is silent in most people until it is at a late stage.) It is the next diabetes.

Mesoblast (MESO):

The next wave of medical advances are going to come through better understanding of immunomodulation. Most if not all diseases-including cardiac disease and diabetes--will come to be understood as inflammatory diseases to be manipulated at the cellular level. We will see more and more of these diseases due to our inflammatory (sedentary, antioxidant-deprived) lifestyle and toxic environment. In any case, I'm interested in the companies who are leading the way in specialized research in immunomodulation. Mesoblast is using stem cell technologies to repair the immune system, and applying that technology to many untreatable diseases.

Avalon GloboCare (AVCO):

Same argument as Mesoblast: multiple technologies, targeted immunotherapy. I'm not so interested in any single technology, but they are partnering on several important technologies (stem cells, diagnostic technologies), with broad implications and clinical uses. They are partnering to develop a nasal vaccine for Covid, but again, I'm not as interested in that particular product, but the broader technology. Nasal vaccines are going to be a winner for many reasons-ease of use, global application, and the fact that we will run short on syringes for other vaccines).

Altimmune (ALT):

Same as above: leader in NASH (non-alcoholic fatty liver disease), nasal vaccine technology

Okay, those are my four picks. Amazing for metastatic cancer, including prostate (though the recent studies are on a hard to treat breast cancer). The others, JNJ, Becton Dickinson, and DaVita, you know."

I love the fact that my daughter comes at investing from an angle so different from mine and with a skill set that does not overlap mine at all. I also love that its method combines brains and a good heart - the assumption that a company is worth the sum of what it contributes to human well being. What I find most intriguing is that her natural way of coming at things aligns so closely with the Adam Smith view. Can growth investing possibly have such a simple foundation?

You will probably have guessed that I have never bought anything like these biotech companies nor used anything resembling this kind of analysis. I do not, and could not possibly, recommend any or all of them. They are well outside my areas of knowledge and expertise. The only counsel I was able to give my daughter included the fact that when buying companies like this you should probably buy a basket of them - something which she had already done, intuitively.

By early July she had tripled her money and was beginning to be worried about what felt to her like an overhyped sector of an overpriced market. This was where she thought my advice might be useful. I laughed and said that she should be giving me financial advice instead of vice versa, but if she was nervous she should probably sell down to her comfort level (she's in a low tax bracket so cap gains aren't a problem). Perhaps she should at least sell down to the point at which she was investing with house money. I added that it was okay to leave a few chips on the table and let her long term bet ride. She agreed and did something close to that.

Her insight had been pretty simple. The value of a company should correspond to the amount of value added via the "invisible hand" to the health, happiness, and well-being of its customers - perhaps even to the general populace. You would start by estimating the size of the market for which it provided a product or service. You would then adjust to take into account the competition for that market and finally the probability of your particular company capturing a major part of that market. Then, and only then, you might begin to make rough estimates as to potential revenues and profit margin. The key correlation is not revenue and profit margin, which are well out in the future, but the value the company is likely to add to society. The payoff in small biotechs like these, if it comes at all, is likely to come in a rush when a large pharma company sees the potential and buys them out, fulfilling the Adam Smith projection of appropriate reward for a large service.

When I started to formulate it this way, I realized that I have missed quite a lot in never owning stocks which might be best measured in this way. This includes not just small biotechs and niche technology startups but also giant current market leaders such as Amazon (AMZN), Netflix (NFLX), and Tesla (TSLA). At every point in the lives of these three companies, I have found that the methods by which I have always valued stocks - things like discounted earnings, dividends, and cash flow - made me unable to put together any reasonable argument for owning them.

Had I finally stumbled upon a valuation model that might provide a rationale for buying them? Up to this point, I have not seen a persuasive methodology for thinking about the value of these companies. Could this simple approach account for their unusually high valuations?

Adam Smith implied that the relationship between a business and the population it served was the invisible force behind what we call capitalism. It takes only a small further step to propose that the population served by a business can also be described as an "asset" owned by that business. In some cases, especially young or innovative companies, it is customers acquired that is the central asset. The idea of a business "owning" its customers is not new. I first read about it in a novel at least fifty years ago when a literary agent retires by essentially selling his customers to a rival - a practice that was apparently commonplace even then.

This customer-based approach seems to be the way the founders of these three market leaders looked at the opportunity. Customers weren't just part of the picture. They were the whole thing. Acquiring customers is what these companies set out to do. Everything else could come later. They were determined to do everything it takes to own the largest number of customers, including running their businesses with negative earnings and free cash flow for a long time. The market caught on to their goals and their prices shot up to the stratosphere.

Amazon, Netflix, and Tesla have always sold at ridiculous multiples of earnings and cash flow, if any, and are ridiculously expensive by pretty much every other traditional measure. When you look at them the way my daughter looks at biotechs, however, the picture changes. You set the standard ratios aside and instead ask: what is the value of these companies if measured by the sum of value they provide in service to their actual and potential customers? The transmission of that value to shareholders is initially as invisible as the invisible hand by which value is distributed to the populace. It is nevertheless reflected in the stock price.

Here's how one might do a broad estimate of value for the three companies:

Today, online commerce saves customers money and precious time," writes Bezos. "Tomorrow, through personalization, online commerce will accelerate the very process of discovery. Amazon.com uses the internet to create real value for its customers and, by doing so, hopes to create an enduring franchise, even in established and large markets.

We believe that a fundamental measure of our success will be the shareholder value we create over the long-term. This value will be a direct result of our ability to extend and solidify our current market leadership position. The stronger our market leadership, the more powerful our economic model.

Because of our emphasis on the long-term, we may make decisions and weigh tradeoffs differently than some companies... We will continue to make investment decisions in light of long-term market leadership considerations rather than short-term profitability considerations or short-term Wall Street reactions...We aren't so bold as to claim that the above is the 'right' investment philosophy, but it's ours, and we would be remiss if we weren't clear in the approach we have taken and will continue to take.

From the beginning, our focus has been on offering our customers compelling value," explained Bezos. "We brought [customers] much more selection than was possible in a physical store (our store would now occupy six football fields), and presented it in a useful, easy-to-search, and easy-to-browse format in a store open 365 days a year, 24 hours a day."

That's Amazon's mission statement summed up in a few paragraphs. The guiding purpose to this business model is positioning yourself to "own" more and more customers. This customer-obsession of Bezos amounts to is a manifesto for innovative companies. The second paragraph flows directly from the core principle of Adam Smith. Get first things first, Bezos is saying, meaning understanding the potential market and seizing it. Profitability and measurements commonly used by Wall Street come later.

Amazon is no longer a young company in chronological age, but the vision embedded in its mission statement is to remain a young company forever. A Day 1 company, as Bezos calls it, is always visionary and entrepreneurial in its thinking. What Bezos is saying to investors is: disregard the numbers used by Wall Street analysts. They are important measures only for Day 2 companies (slow-moving, mature companies in stasis, for which the next stage is death). Keep your eyes on the main thing - the growth of your customer base and a high level of customer satisfaction. Facebook (FB) and Alphabet (GOOG)(GOOGL) were like that in early stages but moved fairly quickly to address the question of how to monetize their users, eventually succeeding and becoming measurable by ordinary metrics. They are now ordinary growth companies with moderately high PEs, at least in context of the current market. Bezos rejected early monetization. Have faith, he said. We will monetize our customer base when we get around to it.

The greatest single risk for Amazon is its increasing size, which makes it difficult to remain nimble and full of energy. At some point, it will face the horror which confronts history's great empires - running out of worlds to conquer. Political constraints may have something to do with that, but pure size is the major burden. Summing it up, I would buy Amazon at something like 50-60% of its present price if nothing had gone wrong in the business in the meantime.

2. Elon Musk somehow manages to top Bezos. His manifesto, much of which comes out in random statements and tweets, is that Tesla will one day produce pretty much every car sold in the US, maybe even the world. At the very least it will be the driving force in a new industry. His business has a powerful technological core, but the rational for it is the prospect of capturing much of the total customer base for vehicles. It currently appears to be priced on the assumption that Musk will succeed in this ambition to a large degree.

Musk is confident that Tesla's technology will become the universal standard and squeeze most of the current auto industry into terminal decline. Its panache stems from great aesthetics and the promise of enlisting his customers in the project of slowing climate change and helping save the world. Tesla, he implies, will almost incidentally become highly profitable, an outcome to which Musk himself seems to be personally indifferent but in which his investors might have some interest. If he is right, Tesla will probably look cheap if bought today or tomorrow at 160 times its current (and first annual) positive earnings.

Like Bezos, Musk would have us remember: we don't care about all that. That's the old valuation model. What we care about is a market of 17 million vehicles sold annually in the US and a number around five times that in the world. That's the scale of customers Elon wants to own. Once that happens, he will bite the bullet and monetize.

To own Tesla at anything like the current price you have to make a few audacious assumptions. You have to believe that vehicles will continue to be bought on very large scale and that the overwhelming number of vehicles sold will become electric within a short period of time. You then have to believe that Tesla will become the company that owns most of the customers and sells most of the vehicles. It's not impossible, but there are obstacles to overcome.

If Ford, GM, Toyota, Honda and others launch a modestly successful counterattack, or the whole market shrinks, you will see the earnings and cash flow multiples of Tesla shares contract in the general direction of the valuations of those "Day 2" companies. In other words, if you are an investor, you don't want Tesla to become just another car company, nor do you want it to be the last giant in an industry that is contracting and possibly dying. If one of those things happens, Tesla, as measured by the Adam Smith premise, is likely to be a disappointing investment. This is very broad brush analysis, but that's the only way to really deal with Tesla, a company quite similar to my daughter's biotechs. The risks for Tesla seem high and hard to calculate. These are the problems routinely faced by innovative companies in their early stages, and you must also pay attention to the risk that Tesla could run out of time to overthrow the industry while the industry still exists in its present form.

3. Netflix is a company I have looked at only recently. Until a few months ago I had never used their product - not once. Entertainment is OK - I'm being entertained by writing this, and I dare to hope that you readers are both entertained and stimulated to further thought by it - but I didn't experience Netflix until a millennial step child and her husband spent some time with us and promptly realized that they couldn't live without it. They put it on a couple of our TVs so that they would have some kiddie movies to bribe their 3-year-old to eat dinner plus an hour of decompressing entertainment for themselves before sleep.

A few months ago my wife and discovered that we still had it, linked somehow to their home two thousand miles away, and it turns out that the shows are pretty good. They turned out to be especially valuable during the lockdown. We had run out of old movies, so we started over with Netflix. I started paying attention to articles on Netflix and ultimately took a look at their numbers.

Egads! They have been unprofitable from day one and their negative cash flow has done nothing but increase. Their costs for content are going up and their competition is mounting. On the other hand, Stranger Things is the kind of nitwit escapism that I found that I like after a long hot day teaching tennis (my wife not so much).

How do I put the two views of Netflix together. In this case, the risks and uncertainties make the stock uninvestable for me. For one thing, I am used to having entertainment piped into me for free (I automatically tune out all ads.) The numbers needed are just too daunting for Netflix, the rising costs for content are worrisome, and ultimate limits in a market now sliced several ways implies limits to growth. I am doubtful that Netflix will ever morph into a company I can measure more conventionally. I'm pretty sure I wouldn't renew if our faraway relatives stopped providing it for free. That's the core of it: I'm a customer of sorts, but they don't really own me. I don't own them either, and am not likely to any time soon.

The outperformance of high growth companies over the last decade and most spectacularly over recent months has naturally invited vigorous debate. The catastrophic dot.com crackup exactly two decades ago has receded sufficiently that alt explanations of market behavior are once again beginning to be proposed in earnest. This article is perhaps one of them but exists within the frame of traditional methods.

The dot.com era which reached its peak in 2000 crashed amidst assertions that eyeballs and clicks were better measures of value than earnings or cash flow. I lived through it as a bystander, listening to fellow fitness enthusiasts in the workout room at my tennis club boast about their portfolios, then noticing their absences one by one as the crisis unfolded. I didn't feel schadenfreude, far from it, only relief that I myself had not been ruined.

Valuations are once again at a point which calls ordinary prudence into question. Are the traditional models of valuation no longer worth using? This was suggested recently by BlackRock quant Jeff Shen who argued here that traditional efforts to solve the "mystery" of value are worthless. The Shen view, by the way, derives from this article by another BlackRock analyst, Gerald T Garvey, published in the prestigious Journal of Portfolio Management. The Garvey article comes down firmly on the growth side of the growth/value debate arguing that "elevated percentage value spreads predict higher risk, not higher returns."

In more down to earth terms, Shen and Garvey are saying that companies whose shares haven't been able to grow in this environment are losing ground and possibly dying, and should be avoided. If a stock goes up a lot it is probably safe because the wisdom of crowds is behind its rise. This is the kind of statement that is true until it isn't. Shen goes on to argue that contemporary investors should look for alt indicators and models such as the happiness of a company's employees. That particular idea didn't exactly blow me away, and neither Bezos nor Musk seem to be proponents of using that principle to focus or drive their businesses.

On the other hand, an effort to measure a company's success in terms of the overall value it provides to its customers does seem to me an interesting way to think about growth companies. Most companies trading in the aftermarket for stocks - by now you know that when I use this awkward but accurate phrase I am referring to the "stock market" - are not high growth companies and are probably best analyzed by traditional measures. Ultimately some form of traditional value measurement must appear within the life-cycle of a successful company.

To Jeff Bezos, the moment when traditional cash measures become important to a company is the day that it wakes up as a Day 2 company, a company that does not attempt to reinvent the world afresh every morning. While such a company may still turn out to be a decent investment, it's important for value investors to pay careful attention to their risk of having their business disrupted by new technologies and methods. This is a fairly straightforward way of thinking about the world we now live in, and I have learned to ask the hard questions about everything I own - even companies with seemingly strong moats.

Disruption is a major theme of the contemporary world, and every thoughtful person would do well to put the world together afresh every morning. Even with an open mind, it's hard to anticipate what hidden risks might cause a company's current defenses to collapse. Because of the incredible speed of change and the prevalence of unsuspected collateral effects, this questioning is important in a way that it has never been in the past. That was the important lesson number two from the dot.com event. Buying the disruptors rarely made fortunes, but not being sufficiently cautious about potential disruptees was a good way to lose a fortune.

For these businesses the Adam Smith Model needs to be turned upside down so that it becomes a story about loss of customers. One of the great anecdotal examples was Bill Gates stunning a 1990s gathering of Buffett's value investor pals by using his knowledge of the digital world to inform them that Eastman Kodak (KODK), then a market stalwart, was "toast." The customer criterion proves its importance when inverted. I was unable to estimate the outcome for Amazon - haven't made a nickel directly by buying it - but it was obvious to me instantly that it was going to be the end of the road for many other retailers, as well as many malls and REITs. The history of Sears Roebuck and Walmart were powerful precedents. The only thing not entirely clear was the time frame, which is proving to be much faster than most people expected.

The astonishing thing was how eagerly investors jumped on the Amazon bandwagon, which has many uncertainties, and how slowly the investor mind adjusted to the knock-on effects, which were far more certain. The key to grasping this quickly, is to focus on customers "owned" but sure to slip away, as in the case of Kodak.

The Adam Smith Model is simply one of the ways of making an estimate concerning what the cumulative value should be somewhere down the road at whatever time the company decides to monetize the cash value of owning its customer base. At that point, it will begin to report profits and cash flow, pay dividends, and buy back shares. Apple (AAPL) may be the best current example of this model. It started paying dividends and buying back shares about a year before its growth began to level off. As the dream of perpetual growth disappeared, investors were rewarded by the cold cash that abundantly flowed.

This is the distant event that Bezos' mission statement grudgingly projects. For Bezos, earnings, dividends, and buybacks are Day 2 concerns, and you get the feeling that he would just as soon not live to see them. Being a Day 2 company, is like living a comfortable and happy life: the great second-best award for those who have given up their aspirations to greatness. So Apple was once an innovative company priced on the basis of the Adam Smith Model and has now normalized into a Day 2 company which can be valued by the traditional tools. Who knows, maybe it has a few positive tricks up its sleeve but relentless regular growth is a thing of the past.

Amazon seems to be on the same general course as Apple, but with ordinary shareholder gratification deferred into a less well defined and more distant future. You just have to wait for it, and at an incredibly low discount rate such as the current Treasury rates you are willing to pay up for the ultimate awards now and wait a long time. This is part of the current market infatuation with rapid and persistent growth. If you project very far into the future, the value may approach infinity, or since that concept no longer exists even in physics, you could approximate it by the difficulty Amazon would have if Amazon's business became the major part of the gross product of the planet.

High valuations in the current market can be partially explained by a number of factors including historically low interest rates and the appeal of the tech leaders during a broad public lockdown. It also true, however, that the most optimistic thinking stems from a gambling mentality which is supported by the famous Petersburg Paradox which has come to bear in their valuations. There are a number of recent articles with varied approaches to this subject, and you can sample them by googling Petersburg Paradox.

The Petersburg Paradox is generally credited to Daniel Bernoulli, who published an article on it in 1738, but is sometimes credited to his cousin Nicolaus Bernoulli who talked about it in a letter written in 1713. It is a simple gambling game that doubles your winnings with each successive throw of tails. Its expected return generates an infinite series of events the probability of which decline by the exponential 1/2 to the N power exactly offsetting the exponential increase in winnings (2 to the N power).

Each successive term is exactly 1. The mathematically expected return is the sum of that infinite number of ones. I suppose that this means you max out when the number in dollars is equal to the number of bits (or Planck units) in the universe.

This series, therefore, produces quite large expectation of winnings despite the fact that the probability of large winnings at any particular future point obviously diminishes enormously and becomes very slight after a few coin tosses. It is famous for the contradiction of the expected total return and the relatively small amount that any reasonable person would be willing to wager on that return. A number of mathematicians have attempted to resolve this contradiction - economist and quant Paul Samuelson having been one of them - but their efforts at refutation have been unsatisfying.

Recent articles have related the Petersburg Paradox to investor expectations for stocks with high and persistent earnings growth. An extremely smart and interesting article was published way back in 1957 by David Durand (The Journal of Finance, Vol 12, No 3, Sep 1957, pp 348-363). Durand explored the problem of valuation for growth stocks including the then relatively new approach of using multiple discount rates at various break points in time. The growth numbers are quaint - annual growth at numbers like 5 and 6.5% - chickenfeed compared to growth rates of modern high tech companies.

Durand related the question of pricing long growth periods to the Petersburg Paradox, addressing the infinity problem and the need to truncate the infinite series at some point. This has a parallel to the problem of valuing current growth companies where it is necessary to consider not only forecasts for future earnings growth rates but also the length of waiting time before cash flows and dividends appear. There's also the question of the interest rate used for discounting, which is now virtually nil but has been very significant at times in the past.

The Adam Smith Model happens to dovetail nicely with the distant outcomes of the Petersburg Paradox coin flip game. The further away the payout is from the present the larger the rewards become when you finally throw heads. It's just that in the case of fast growing but not yet profitable companies, you more or less defer the chance of hitting heads early in order to let the reward build exponentially and have the promise of hitting a very large summative outcome in the future. That's where the thinking of investors in Amazon, Tesla, and Netflix must come from, and it's more or less rational if their estimate of the payoff and the time necessary to achieve it are reasonably accurate. It has been pretty accurate in the case of Apple.

There's just one more thing, of course. What if the estimate of Adam Smith value proves to be outright wrong? What if a tough new competitor with a better technology or improved business model appears? What if competition already in place proves to be more formidable than assumed? Even with Amazon these risks must be taken into account, but with Tesla they should be major concerns, and with Netflix they should be very major concerns.

There could also be exogenous risks such as a major rise in interest rates which would wreck the denominator and greatly reduce the value of a distant payoff. That high denominator, by the way, was what drove price earnings ratios in the 1970s down to the single digits. Returns even a few out years were so heavily discounted that no one wanted to look that far into the future. This sort of thinking served to greatly diminish the appeal of growth stocks.

Innovative companies don't always work out. I thought about that a lot around the year 2000, when I attached a 95% probability to my belief that the investing world had lost its collective mind but reserved a 5% probability I was the one who just didn't get it. The odd thing is that some of the new model dot.coms did, in fact, contribute quite a bit to the general welfare. They made all sorts of businesses more efficient, and at the same time made basic communication for everyone cheaper, faster, and better. This is presumably a good thing. In the end, however, it didn't work out well for shareholders who held on long term.

But there's another question. Did their temporarily outrageous valuations represent a magical mechanism for pulling forward a proper reward for founders and the most nimble shareholders despite the fact that the companies themselves were destined to never ultimately earn any money? In a just version of Adam Smith's invisible handsome reward was certainly owed to the founders and early owners who contributed so much to human well being but the mechanism by which they received it is somewhat murky,

So what if that deferred payoff never comes?

Schopenhauer asked a similar question in his Studies in Pessimism, except that he asked it about death, not a sudden gush of cash flow. Calm down, Schopenhauer argued. Why fear death? If you knew it wasn't the end of things, that you would wake up tomorrow morning feeling fine, you wouldn't worry about it much. What about waking up next week? What about next year? What about five or ten years out? What about a thousand years before you wake up? Ten thousand? What about... never? Would it make a difference?

Schopenhauer's courage in the face of non-being is reflected in the large number of investors who seem unworried about the possible absence of cash returns many years into the future. Once you take the Schopenhauer premise, it doesn't matter if the payoff never arrives. The stock is going up today in anticipation of it. That's all that really matters. Shareholders are happy. You can always cash out at your convenience. What is the future anyway but a dwindling infinite series?

It's really more like heaven than death. Both of my grandmothers believed strongly in its existence, although I can't imagine what they really thought it would be like. It probably didn't matter. In both cases, it sustained them over the course of long and productive lives which they lived with great confidence of a wonderful if not precisely defined eternity. Ignorance was bliss.

A business is its customers. Is it as simple as that? The value of a business is the value of the services provided to its present and prospective customers discounted for the distance in time to monetization of those customers but discounted to reflect the possibility of various things that could happen to reduce or wipe out that future payoff. Both new and rapid growth businesses generally defer that payout further into the future than most businesses, especially if the discounting factor is relatively low.

This model produces huge winners and abject losers. We marvel at the winners when we see them without considering survivor bias. We discard the losers even if they have played a major part in the evolution of the economic world and traded at high prices in optimistic moments along the way. In retrospect we wonder why they once traded at such high prices.

In very young industries such as biotechs, the outcome often leaves losers by the way side and rewards just one or two competitors. One way of thinking about this is that at the outset many such companies own a similar probability of surviving but one or two end up "owning" most of the customers and the cash flow bonanza that will eventually come with them. The probability of winning gradually shrinks for most but rises for the winners. For that reason, my daughter's approach of buying a basket of these companies is probably the best way for investors to participate.

This approach may also be very helpful in evaluating growth companies which are not new but remain at some distance from giving investors serious cash rewards. Here the method for selecting a basket of winners draws upon the kind of broad-brush estimates and calculations used in selecting a basket of small biotechs. If looking closely at Amazon, Tesla, and Netflix doesn't help much, it's important to make and constantly update estimates bearing upon the scale and strength of their "ownership" of customers as well as rough estimates of risks. This broad and approximate approach is how Adam Smith would probably have looked at valuation of companies if he was as interested in profits as we sometimes assume him to have been.

Disclosure: I am/we are long JNJ, BDX. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

Read the rest here:
How Adam Smith Might Have Valued Amazon, Netflix, Tesla, And Tiny Biotechs - Seeking Alpha

Cardiac Stem Cells Comments Off on How Adam Smith Might Have Valued Amazon, Netflix, Tesla, And Tiny Biotechs – Seeking Alpha | August 10th, 2020

August 4, 2020 - More than three years after a clinical trial was prematurely ended for failing to show progress in healing heart attack scars, the European Heart Journal publishing some surprising results showing that the heart cell treatment does benefit patients.[1]

Data from the ALLSTAR study published Tuesday by the European Heart Journal showed that although infusions of allogeneic cardiac cells (called cardiosphere-derived cells or CDCs) did not appear to shrink the infarct scar after a heart attack, other data from the study show a clear benefit.

Compared with patients who received placebo treatment, patients randomized to receive CDC infusions showed a decrease in the volume of blood in the heart before and after it beats, indicating that the heart had not dilated, as it does progressively in heart failure.

"As it develops heart failure, the heart gets bigger and bigger, like a swelling balloon," said the study's lead author, Raj Makkar, M.D., vice president of cardiovascular innovation and intervention for Cedars-Sinai and the Stephen R. Corday, M.D., chair in interventional cardiology. "One way we can measure the health of a heart is to measure the volume of blood it can hold. The bigger the volume, the more damaged the heart."

The newly analyzed data from the ALLSTAR study, which was sponsored by Capricor Therapeutics, showed that patients given a placebo had hearts that continued to swell, holding larger volumes of blood, while the patients who received CDC infusions had smaller hearts with lower volumes.

The new data results include:

The volume of blood held by the heart was essentially unchanged six months after CDC infusion, but increased by more than a teaspoonful in placebo patients.

A blood protein that measures heart failure severity was reduced in patients who had received CDCs, but not in placebo patients.

The chance that these findings were statistical flukes was only 2 percent.

"To me, these data are very reassuring that there really is therapeutic benefit," said Eduardo Marbn, M.D., Ph.D., executive director of the Smidt Heart Institute. "There is a growing body of evidence that this cell treatment does work."

Results from the earlier CADUCEUS trial, published in The Lancet in 2014, showed that injecting CDCs into the hearts of heart attack survivors significantly reduced infarct size. In 2017, however, the multicenter ALLSTAR study was prematurely halted after six months of data showed no decrease in heart attack scar size, but later analyses revealed the beneficial findings reported here.

"We think we may have chosen the wrong endpoint," said Marbn, the Mark S. Siegel Family Foundation Distinguished Professor, whose discoveries and technologies resulted in CDCs. "This happens in science because you have to design the trial a year or more before you begin, and sometimes you bet on the wrong hors... but that doesnt necessarily mean the therapy is ineffective."

The cells used in the study were CAP-1002, Capricor Therapeutics off-the-shelf, cardiosphere-derived cell (CDC) product candidate. Other clinical trials and case series, in which CDCs were used to treat advanced heart failure, Duchenne Muscular Dystrophy, and COVID-19, also demonstrated positive results. And new studies using CDCs are in the planning stages.

"California is known as the stem cell state, but few technologies being tested in California actually were developed here," said Shlomo Melmed, MB, ChB, executive vice president of Academic Affairs, dean of the Medical Faculty and professor of Medicine. "Increasing evidence-including the results of the large multicenter ALLSTAR trial-validates the potential utility of a cell product which was conceived by a faculty member at Cedars-Sinai, and first tested clinically here."

Read the complete study published by the European Heart Journal.

Disclosures: Except for the cells used in CADUCEUS, the cardiosphere-derived cells used in these studies were derived from donor hearts and provided by Capricor Therapeutics. Marbn developed the process to grow CDCs when he was on the faculty of Johns Hopkins University; the process was further developed at Cedars-Sinai. Capricor has licensed the process from Johns Hopkins and from Cedars-Sinai for clinical and commercial development. Capricor has licensed additional intellectual property from Cedars-Sinai and the University of Rome. Cedars-Sinai and Marbn have financial interests in Capricor.

Reference:

1. Raj R Makkar, Dean J Kereiakes, Frank Aguirre, et al. Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR): a randomized, placebo-controlled, double-blinded trial. European Heart Journal, ehaa541, https://doi.org/10.1093/eurheartj/ehaa541.

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Three Years After Stem Cell Trial for Heart Failure was Abandoned New Evidence Shows it Works - Diagnostic and Interventional Cardiology

Cardiac Stem Cells Comments Off on Three Years After Stem Cell Trial for Heart Failure was Abandoned New Evidence Shows it Works – Diagnostic and Interventional Cardiology | August 10th, 2020

Stem cells have been holding great promise for regenerative medicine for ages. In the last decade, many studies have revealed this form of cell, which in Spanish is calledmother cell due to its ability to contribute to various different cell types, may be applied in regenerative medicine to diseases such as muscle and nervous system disorders, among others.

Scientists and stem cell leaders Sir John B. Gurdon and Shinya Yamanaka received the Nobel Prize in Physiology and Medicine in 2012 for this idea.

However, one of the key constraints in the application of these herbal remedies is the caliber of the stem cells that may be made in the lab, which impedes their use for curative purposes.

Currently, a team in the Cell Division and Cancer Group of the Spanish National Cancer Research Centre (CNIO), headed by researcher Marcos Malumbres, has recently developed a fresh, easy and fast technology that enhances in vitro and in vivo the possibility of stem cells to differentiate into adult cells. The study results will be released this week in The EMBO Journal.

In recent years, several protocols have been proposed to obtain reprogrammed stem cells in the laboratory from adult cells, but very few to improve the cells we already have.The method we developed is able to significantly increase the quality of stem cells obtained by any other protocol, thus favouring the efficiency of the production of specialised cell types.Mara Salazar-Roa, Study First Author and Researcher, Centro Nacional de Investigaciones Oncolgicas

Roa is likewise the co-corresponding author of this analysis.

Within this study, the researchers identified an RNA sequence, called microRNA 203, that can be found at the earliest embryonic stages before the embryo implants in the uterus and when stem cells have their highest ability to generate all the different cells.When they added this molecule to stem cells from the laboratory, they discovered that the cells ability to convert into other cell types improved appreciably.

To corroborate them, they used stem cells of both human and murine origin, and of genetically altered mice. The results were so spectacular, both in mouse cells and in human cells

Application of the microRNA for just 5 days boosts the potential of stem cells in most situations we tested and improves their ability to become other specialised cells, even months after being connected with the microRNA. Says Salazar-Roa.

According to the research, cells modified by this new protocol are more efficient in generating functional cardiac cells, opening the doorway to a better generation of different cell types essential for the cure of degenerative disorders.

Malumbres, mind of the CNIO Cell and Cancer Division Group, states:To deliver this asset to the clinic, cooperation with labs or companies that are looking to exploit that technology is now essential in each particular case.

In this circumstance, Salazar-Roa recently participated, in close collaboration with all the CNIOs Innovation group, in prestigious creation programs like IDEA2 International of the Massachusetts Institute of Technology (MIT) and also CaixaImpulse of thisLa Caixa Foundation, where they also obtained funding to start the maturation of the technology.

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New technology May Raise the quality of stem cells Found in regenerative medicine - Microbioz India

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