Steve Perrin, Ph.D., CEO and CSO, discusses why iPS technology is ready for drug discovery for today's ALS patients. Click here to learn why Steve believes TDI is uniquely suited to implement this technology in ALS research.

Fernando Vieira, M.D., director of research operations, discusses how iPS technology can be used to model sporadic ALS, help to identify sub-types of ALS patients and accelerate drug development as part of a comprehensive translational research program at ALS TDI.

Jessie St. Martin, associate scientist, talks about induced pluripotent stem cells (iPS cells) and their importance in ALS research. Jessie, a recent addition to the translational research team, will play an integral part in developing this program at ALS TDI. Click here to learn more about iPS cells.

Jenny Dwyer, board member, explains why your support of the iPS program at ALS TDI may have the ability to rapidly accelerate treatments for today's patients. Jenny was a longtime ALS caregiver of her husband, Pat. Together, they were advocates for ALS research. Click here to listen to her message.

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Invest in iPS @ TDI | ALS Therapy Development Institute

1 Control of Pluripotency Laboratory, Department of Physiological Sciences I, Faculty of Medicine, University of Barcelona, Hospital Clinic, Casanova 143, 08036, Barcelona, Spain 2 Faculty of Medicine, University of Sydney Medical School, Division of Pediatrics and Child Health, Westmead Children's Hospital, Locked Bag 4001, Westmead NSW 2145, Sydney, Australia 3 School of Anatomy Physiology & Human Biology and The Harry Perkins Institute for Medical Research (CCTRM), the University of Western Australia, 6 Verdun St, Nedlands WA 6009, Perth, Australia

* Author to whom correspondence should be addressed.

Received: 1 October 2014 / Accepted: 3 December 2014 / Published: 29 January 2015

Abstract: The use of adult myogenic stem cells as a cell therapy for skeletal muscle regeneration has been attempted for decades, with only moderate success. Myogenic progenitors (MP) made from induced pluripotent stem cells (iPSCs) are promising candidates for stem cell therapy to regenerate skeletal muscle since they allow allogenic transplantation, can be produced in large quantities, and, as compared to adult myoblasts, present more embryonic-like features and more proliferative capacity in vitro, which indicates a potential for more self-renewal and regenerative capacity in vivo. Different approaches have been described to make myogenic progenitors either by gene overexpression or by directed differentiation through culture conditions, and several myopathies have already been modeled using iPSC-MP. However, even though results in animal models have shown improvement from previous work with isolated adult myoblasts, major challenges regarding host response have to be addressed and clinically relevant transplantation protocols are lacking. Despite these challenges we are closer than we think to bringing iPSC-MP towards clinical use for treating human muscle disease and sporting injuries.

Roca, I.; Requena, J.; Edel, M.J.; Alvarez-Palomo, A.B. Myogenic Precursors from iPS Cells for Skeletal Muscle Cell Replacement Therapy. J. Clin. Med. 2015, 4, 243-259.

Roca I, Requena J, Edel MJ, Alvarez-Palomo AB. Myogenic Precursors from iPS Cells for Skeletal Muscle Cell Replacement Therapy. Journal of Clinical Medicine. 2015; 4(2):243-259.

Roca, Isart; Requena, Jordi; Edel, Michael J.; Alvarez-Palomo, Ana B. 2015. "Myogenic Precursors from iPS Cells for Skeletal Muscle Cell Replacement Therapy." J. Clin. Med. 4, no. 2: 243-259.

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IMAGE:Induced pluripotent stem cell-derived motor neurons from an ALS patient (left) compared with normal cells (right). The cells are being used to study the role of the genes TBK1 and... view more

NEW YORK, NY (February 19, 2015)--Using advanced DNA sequencing methods, researchers have identified a new gene that is associated with sporadic amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease. ALS is a devastating neurodegenerative disorder that results in the loss of all voluntary movement and is fatal in the majority of cases. The next-generation genetic sequencing of the exomes (protein-coding portions) of 2,874 ALS patients and 6,405 controls represents the largest number of ALS patients to have been sequenced in a single study to date.

Though much is known about the genetic underpinnings of familial ALS, only a handful of genes have been definitively linked to sporadic ALS, which accounts for about 90 percent of all ALS cases. The newly associated gene, called TBK1, plays a key role at the intersection of two essential cellular pathways: inflammation (a reaction to injury or infection) and autophagy (a cellular process involved in the removal of damaged cellular components). The study, conducted by an international ALS consortium that includes scientists and clinicians from Columbia University Medical Center (CUMC), Biogen Idec, and HudsonAlpha Institute for Biotechnology, was published today in the online edition of Science.

"The identification of TBK1 is exciting for understanding ALS pathogenesis, especially since the inflammatory and autophagy pathways have been previously implicated in the disease," said Lucie Bruijn, PhD, Chief Scientist for The ALS Association. "The fact that TBK1 accounts for one percent of ALS adds significantly to our growing understanding of the genetic underpinnings of the disease. This study, which combines the efforts of over two dozen laboratories in six countries, also highlights the global and collaborative nature of ALS research today.

"This study shows us that large-scale genetic studies not only can work very well in ALS, but that they can help pinpoint key biological pathways relevant to ALS that then become the focus of targeted drug development efforts," said study co-leader David B. Goldstein, PhD, professor of genetics and development and director of the new Institute for Genomic Medicine at CUMC. "ALS is an incredibly diverse disease, caused by dozens of different genetic mutations, which we're only beginning to discover. The more of these mutations we identify, the better we can decipher--and influence--the pathways that lead to disease." The other co-leaders of the study are Richard M. Myers, PhD, president and scientific director of HudsonAlpha, and Tim Harris, PhD, DSc, Senior Vice President, Technology and Translational Sciences, Biogen Idec.

"These findings demonstrate the power of exome sequencing in the search for rare variants that predispose individuals to disease and in identifying potential points of intervention. We are following up by looking at the function of this pathway so that one day this research may benefit the patients living with ALS," said Dr. Harris. "The speed with which we were able to identify this pathway and begin our next phase of research shows the potential of novel, focused collaborations with the best academic scientists to advance our understanding of the molecular pathology of disease. This synergy is vital for both industry and the academic community, especially in the context of precision medicine and whole-genome sequencing."

"Industry and academia often do things together, but this is a perfect example of a large, complex project that required many parts, with equal contributions from Biogen Idec. Dr. Tim Harris, our collaborator there, and his team, as well as David Goldstein and his team, now at Columbia University, as well as our teams here at HudsonAlpha, said Dr. Myers. "I love this research model because it doesn't happen very frequently, and it really shows how industry, nonprofits, and academic laboratories can all work together for the betterment of humankind. The combination of those groups with a large number of the clinical collaborators who have been seeing patients with this disease for many years and providing clinical information, recruiting patients, as well as collecting DNA samples for us to do this study, were all critical to get this done."

Searching through the enormous database generated in the ALS study, Dr. Goldstein and his colleagues found several genes that appear to contribute to ALS, most notably TBK1 (TANK-Binding Kinase 1), which had not been detected in previous, smaller-scale studies. TBK1 mutations appeared in about 1 percent of the ALS patients--a large proportion in the context of a complex disease with multiple genetic components, according to Dr. Goldstein. The study also found that a gene called OPTN, previously thought to play a minor role in ALS, may actually be a major player in the disease.

"Remarkably, the TBK1 protein and optineurin, which is encoded by the OPTN gene, interact physically and functionally. Both proteins are required for the normal function of inflammatory and autophagy pathways, and now we have shown that mutations in either gene are associated with ALS," said Dr. Goldstein. "Thus there seems to be no question that aberrations in the pathways that require TBK1 and OPTN are important in some ALS patients."

The researchers are currently using patient-derived induced pluripotent embryonic stem cells (iPS cells) and mouse models with mutations in TBK1 or OPTN to study ALS disease mechanisms and to screen for drug candidates. Several compounds that affect TBK1 signaling have already been developed for use in cancer, where the gene is thought to play a role in tumor-cell survival.

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New ALS gene and signaling pathways identified

CHICAGO -- The International Society for Stem Cell Research's 13th annual meeting will take place June 24-27, 2015 at the Stockholmsmssan Exhibition and Convention Center in Stockholm, Sweden. The meeting will bring together approximately 4,000 stem cell scientists, bioethicists, clinicians and industry professionals from over 50 countries to present and discuss the latest discoveries and technologies within the field.

"The ISSCR is excited to bring its annual meeting to Stockholm, a city that shares our passion and reputation for great scientific research and collaboration," said ISSCR President Rudolf Jaenisch, M.D., Whitehead Institute for Biomedical Research. "We look forward to learning more about the strong work being done in Sweden and across Europe."

The meeting will open with the Presidential Symposium on June 24 from 1:15-3:15 p.m. local time. The symposium sets the stage for the meeting with world renowned speakers, including Nobel Prize winner Shinya Yamanaka. It is also the platform for the formal recognition of the 2015 recipients of the McEwen Award for Innovation and the ISSCR Public Service Award. Another prestigious award, the ISSCR-BD Biosciences Outstanding Young Investigator Award, will be presented during Plenary VI on June 27 from 9-11:20 a.m. and followed by an award lecture.

"I look forward to the Presidential Symposium setting the tone for the entire program," Jaenisch said. "A thread throughout will be the use of stem cells to drive our understanding of development and disease, as we explore disease modeling, gene and tissue engineering technologies and other important advances that are bringing stem cells into the clinic."

Presidential Symposium speakers will include:

Fred H. Gage, Ph.D., Salk Institute for Biological Sciences, U.S.

Jrgen Knoblich, Ph.D., Institute of Molecular Biotechnology, Austria

Shinya Yamanaka, M.D., Ph.D., Center for iPS Cell Research & Application, Japan

Jeannie Lee, M.D., Ph.D., Massachusetts General Hospital, U.S.

The McEwen Award for Innovation award winners (Presidential Symposium):

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The International Society for Stem Cell Research announces annual meeting details

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Newswise NEW YORK, NY (February 27, 2015) Researchers have for the first time successfully converted adult human skin cells into neurons of the type that regulate appetite, providing a patient-specific model for studying the neurophysiology of weight control and testing new therapies for obesity. The study, led by researchers at Columbia University Medical Center (CUMC) and at the New York Stem Cell Foundation (NYSCF), was published last month in the online issue of the Journal of Clinical Investigation.

In a separate study, which appeared in the February 10 issue of the journal Development, Kevin Eggan, PhD, Florian Merkle, and Alexander Schier of Harvard University have also succeeded in creating hypothalamic neurons from iPS cells. These neurons help to regulate behavioral and basic physiological functions in the human body, including, in addition to appetite, hypertension, sleep, mood, and some social disorders. The investigators at Columbia and Harvard shared ideas during the course of the research, and these studies are co-validating.

Mice are a good model for studying obesity in humans, but it would better to have human cells for testing. Unfortunately, the cells that regulate appetite are located in an inaccessible part of the brain, the hypothalamus. So, until now, weve had to make do with a mouse model or with human cells harvested at autopsy. This has greatly limited our ability to study fundamental aspects of human obesity, said senior author Rudolph L. Leibel, MD, the Christopher J. Murphy Memorial Professor of Diabetes Research, professor of pediatrics and medicine, and co-director of the Naomi Berrie Diabetes Center at CUMC.

To make the neurons, human skin cells were first genetically reprogrammed to become induced pluripotent stem (iPS) cells. Like natural stem cells, iPS cells are capable of developing into any kind of adult cell when given a specific set of molecular signals in a specific order. The iPS cell technology has been used to create a variety of adult human cell types, including insulin-producing beta cells and forebrain and motor neurons. But until now, no one has been able to figure out how to convert human iPS cells into hypothalamic neurons, said co-author Dieter Egli, PhD, assistant professor of pediatrics (in developmental cell biology), a member of the Naomi Berrie Diabetes Center, and a senior research fellow at NYSCF.

This is a wonderful example of several institutions coming together to collaborate and advance research in pursuit of new therapeutic interventions. The ability to make this type of neuron brings us one step closer to the development of new treatments for obesity, said Susan L. Solomon, CEO of NYSCF.

The CUMC/NYSCF team determined which signals are needed to transform iPS cells into arcuate hypothalamic neurons, a neuron subtype that regulates appetite. The transformation process took about 30 days. The neurons were found to display key functional properties of mouse arcuate hypothalamic neurons, including the ability to accurately process and secrete specific neuropeptides and to respond to metabolic signals such as insulin and leptin.

We dont think that these neurons are identical to natural hypothalamic neurons, but they are close and will still be useful for studying the neurophysiology of weight control, as well as molecular abnormalities that lead to obesity, said Dr. Leibel. In addition, the cells will allow us to evaluate potential obesity drugs in a way never before possible.

This shows, said Dr. Eggan, how improved understanding of stem cell biology is making an impact on our ability to study, understand, and eventually treat disorders of the nervous system. Because there are so few hypothalamic neurons of a given type, they have been notoriously difficult to study. The successful work by both groups shows that this problem has been cracked.

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Neurons Controlling Appetite Made From Skin Cells

Jeanne Loring holds a petri dish with induced pluripotent stem cells from a Parkinsons patient.

A nine-year legal challenge to human embryonic stem cell patents ended Tuesday, when the Supreme Court declined to hear the case.

The decision means the Wisconsin Alumni Research Foundation, or WARF, will get to keep its patent rights for the cells, which were discovered in 1998 by University of Wisconsin - Madison scientist James Thompson.

However, the challengers succeeded in preventing WARF from gaining rights over another important type of stem cells called induced pluripotent stem cells, said Jeanne Loring, a stem cell scientist at The Scripps Research Institute in La Jolla who was part of a coalition contesting the WARF patents.

IPS cells act much like human embryonic stem cells, and are being researched as an alternative for stem cell therapy. Loring is working with a group that seeks to use them to treat Parkinson's disease.

WARF maintains it has the right to license use of human embryonic stem cells, because Thompson developed the methods to isolate them from embryos, which had not been previously done. Loring said the derivation is an obvious extension of methods used to derive non-primate embryonic stem cells, and therefore not patentable.

Loring and two public interest groups, Consumer Watchdog and the Public Patent Foundation, challenged the patents in 2006, and in 2007 succeeded in narrowing WARF's claims to exclude the IPS cells. Loring and the groups continued the challenge on the grounds that as a product of nature, human embryonic stem cells are not patentable.

The U.S. Patent and Trade Office turned down that challenge, and the case reached the Supreme Court last year. By not hearing the case, the Supreme Court let that decision stand.

"They still own human embryonic stem cells," Loring said. "But the way their patents were originally written, they would have also been able to own IPS cells. If there's one success that I would point to, that was worth all the effort, it's that they can't. And the reason they can't is because we challenged the patent."

Calls and an email sent Tuesday to WARF headquarters in Madison, Wis., were not immediately returned.

Read more:
Supreme Court rejects stem cell patent case

Kyoto University Hospital says it will open a center to conduct clinical studies on induced pluripotent stem cell therapies in 2019 year.

Officials said the 30-bed ward will test the efficacy and safety of the therapies on volunteer patients.

The hospital aims to break ground at the site next February and complete construction by September 2019.

As an iPS cell research hub, we hope to apply (the cells) to groundbreaking therapies and make developments in the field of drug discovery, the hospital said in a statement Monday.

Ongoing research on iPS cells at Kyoto University includes turning the cells into dopamine-releasing neurons for transplant into patients with Parkinsons disease, and creating a formulation of platelets that helps blood to clot.

Professor Shinya Yamanaka, who shared the 2012 Nobel Prize in medicine, leads the existing iPS cell research center at Kyoto University.

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Kyoto University Hospital to open iPS cell therapy center in 2019

Hepatology. Author manuscript; available in PMC 2011 May 1.

Published in final edited form as:

PMCID: PMC2925460

NIHMSID: NIHMS221023

Recent advances in induced pluripotent stem (iPS) cell research significantly changed our perspective on regenerative medicine. Patient specific iPS cells have been derived not only for disease modeling but also as sources for cell replacement therapy. However, there have been insufficient data to prove that iPS cells are functionally equivalent to hES cells or safer than hES cells. There are several important issues which need to be addressed and foremost are the safety and efficacy of human iPS cells from different origins. Human iPS cells have been derived mostly from cells originated from mesoderm, with a few cases from ectoderm. So far there has been no report of endoderm derived human iPS cells, preventing comprehensive comparative investigations on the quality of human iPS cells from different origins.

Here we show for the first time reprogramming of human endoderm derived cells (i.e. primary hepatocytes) to pluripotency. Hepatocyte-derived iPS cells appear indistinguishable from human embryonic stem cells in colony morphology, growth properties, expression of pluripotency-associated transcription factors and surface markers, and differentiation potential in embryoid body formation and teratoma assays. In addition, these cells were able to directly differentiate into definitive endoderm, hepatic progenitors, and mature hepatocytes. The technology to develop endoderm derived human iPS cell lines, together with other established cell lines, will provide a foundation to elucidate the mechanisms of cellular reprogramming and to study the safety and efficacy of differentially originated human iPS cells for cell therapy. For studying liver disease pathogenesis, this technology also provides a potentially more amenable system to generate liver disease specific iPS cells.

Recent advances in induced pluripotent stem (iPS) cell research have provided great potential for these somatic cell-derived stem cells as sources for cell replacement therapy and for establishing disease models.114 Human iPS cells have been shown to be pluripotent in in vitro differentiation and in vivo teratoma assays, similar to human embryonic stem (hES) cells.914 Disease-specific iPS cell lines have been generated from fibroblasts and blood cells and some of the disease features have been recapitulated in tissue culture after directed differentiation of the iPS cells, demonstrating the power of this technology in disease modeling.13,15 However, several key issues have to be addressed in order for the iPS cells to be used for clinical purposes. First, although pluripotency has been demonstrated, it is premature to claim that iPS cells are functionally equivalent to hES cells. In fact, one study has suggested that iPS cells have distinct protein-coding and microRNA gene expression signatures from ES cells.1 These differences can not be completely explained by the reactivation of transgenes used in the reprogramming process since human iPS cells generated without viral or transgene integration also displayed a different transcriptional signature compared to hES cells.2 Secondly it was demonstrated that human iPS cells retained certain gene expression of the parent cells, suggesting that iPS cells from different origins may possess different capacity to differentiate.2 This issue is important not only for the purposes of generating functional cell types for therapy but also for safety implications. A comprehensive study using various mouse iPS cells has demonstrated that the origin of the iPS cells had a profound influence on the tumor-forming propensities in a cell transplantation therapy model.3 Mouse tail-tip fibroblast-iPS cells (mesoderm origin) showed the highest tumorigenic propensity, whereas gastric epithelial cell- and hepatocyte-iPS cells (both are endoderm) showed lower propensities.3 It is therefore extremely important to establish human iPS cell lines from multiple origins and thoroughly examine the source impact on both the safety issues and their differentiation potentials. In addition, the ability to reprogram human hepatocytes is crucial for developing liver disease models using iPS cells, especially for certain liver diseases carrying acquired somatic mutations which occur only in hepatocytes of patients, but not in other cell types.1620

In the mouse, iPS cells have been generated from derivatives of all three embryonic germ layers, including mesodermal fibroblasts,6 epithelial cells of endodermal origin7 and ectodermal keratinocytes,8 whereas human iPS cells have been produced mostly from mesoderm (fibroblasts and blood cells) or from ectoderm (keratinocytes and neural stem cells).913,21,22 Here we show reprogramming of human primary hepatocytes (endoderm) to pluripotency. Hepatocyte-derived iPS cells appear indistinguishable from human embryonic stem cells in colony morphology, growth properties, expression of pluripotency-associated transcription factors and surface markers, and differentiation potential in embryoid body (EB) formation as well as teratoma assays. In addition these cells were able to directly differentiate into definitive endoderm, hepatic progenitors, and mature hepatocytes.

Our study lays the ground work necessary to elucidate the mechanisms of cellular reprogramming and to study the safety and efficacy of differentially originated human iPS cells in cell therapy.

Primary human hepatocytes were obtained from Lonza plated on collagen 1 and matrigel coated dishes, and cultured in serum containing WEM (Willians' Medium E), Gentamicin, Dexamethasone 10 mM, FBS 5%, L-Glutamine, Hepes 15mM, Insulin 4 mg/ml with 50ng/ml of HGF and EGF. Medium for culturing hES cells and iPS cells is Knockout DMEM supplemented with 20% KOSR, NEAA, 2-ME, GlutaMAX, 6 ng/ml basic fibroblast growth factor (all Invitrogen). hESC lines WA09 (H9) and WA01 (H1) (WiCell) were cultured on irradiated MEF feeder layers in ES medium. This study was done in accordance with Johns Hopkins ESCRO regulations and following a protocol approved by the Johns Hopkins IRB.

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Generation of Endoderm derived Human iPS cells from ...

Characterization of mdx-iPS with DYS-HAC. (a) Morphology of mdx-MEF, mdx-iPS, and mdx-iPS (DYS-HAC) cells. Phase-contrast (left panel) and GFP-fluorescence (right panel) micrographs are shown. (b) Genomic PCR analyses for detecting DYS-HAC in mdx-iPS cells. (c) FISH analyses for mdx-iPS (DYS-HAC) cells. An arrow indicates the DYS-HAC and the inset shows an enlarged image of the DYS-HAC. (d) RT-PCR analyses of ES cellmarker genes, four exogenous transcription factors, and human dystrophin. EGFP and Nat1 were used as internal controls. Primers for DYS 6L/6R, 7L/7R, and 8L/8R detected the isoform of dystrophin expressed in ES and iPS cells. (e) Immunohistochemical analyses of dystrophin in muscle-like tissues of each teratoma. Immunodetection of mouse and human dystrophin (left panel), immunodetection of human-specific dystrophin (middle panel), and GFP micrography (right panel) are shown. The insets show enlarged images of immunohistochemistry. Nanog-iPS- and mdx-iPS-derived teratomas were used as positive and negative controls, respectively. CHO, Chinese hamster ovary; EGFP, enhanced green fluorescent protein; GFP, green fluorescent protein; HAC, human artificial chromosome; iPS, induced pluripotent stem cells; MEF, mouse embryonic fibroblast.

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A powerful "genome editing" technology known as CRISPR has been used by researchers since 2012 to trim, disrupt, replace or add to sequences of an organism's DNA. Now, scientists at Johns Hopkins Medicine have shown that the system also precisely and efficiently alters human stem cells.

In a recent online report on the work in Molecular Therapy, the Johns Hopkins team says the findings could streamline and speed efforts to modify and tailor human-induced pluripotent stem cells (iPSCs) for use as treatments or in the development of model systems to study diseases and test drugs.

"Stem cell technology is quickly advancing, and we think that the days when we can use iPSCs for human therapy aren't that far away," says Zhaohui Ye, Ph.D., an instructor of medicine at the Johns Hopkins University School of Medicine. "This is one of the first studies to detail the use of CRISPR in human iPSCs, showcasing its potential in these cells."

CRISPR originated from a microbial immune system that contains DNA segments known as clustered regularly interspaced short palindromic repeats. The engineered editing system makes use of an enzyme that nicks together DNA with a piece of small RNA that guides the tool to where researchers want to introduce cuts or other changes in the genome.

Previous research has shown that CRISPR can generate genomic changes or mutations through these interventions far more efficiently than other gene editing techniques, such as TALEN, short for transcription activator-like effector nuclease.

Despite CRISPR's advantages, a recent study suggested that it might also produce a large number of "off-target" effects in human cancer cell lines, specifically modification of genes that researchers didn't mean to change.

To see if this unwanted effect occurred in other human cell types, Ye; Linzhao Cheng, Ph.D., a professor of medicine and oncology in the Johns Hopkins University School of Medicine; and their colleagues pitted CRISPR against TALEN in human iPSCs, adult cells reprogrammed to act like embryonic stem cells. Human iPSCs have already shown enormous promise for treating and studying disease.

The researchers compared the ability of both genome editing systems to either cut out pieces of known genes in iPSCs or cut out a piece of these genes and replace it with another. As model genes, the researchers used JAK2, a gene that when mutated causes a bone marrow disorder known as polycythemia vera; SERPINA1, a gene that when mutated causes alpha1-antitrypsin deficiency, an inherited disorder that may cause lung and liver disease; and AAVS1, a gene that's been recently discovered to be a "safe harbor" in the human genome for inserting foreign genes.

Their comparison found that when simply cutting out portions of genes, the CRISPR system was significantly more efficient than TALEN in all three gene systems, inducing up to 100 times more cuts. However, when using these genome editing tools for replacing portions of the genes, such as the disease-causing mutations in JAK2 and SERPINA1 genes, CRISPR and TALEN showed about the same efficiency in patient-derived iPSCs, the researchers report.

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'CRISPR' science: Newer genome editing tool shows promise in engineering human stem cells

How does CDI's technology work? A human biological sample, for example blood or skin, is obtained, and the cells within the sample are grown under appropriate cell culture conditions. In the episomal reprogramming method, vectors containing multiple reprogramming genes are introduced into the cells.

While the vectors turn genes in the cell on and off, reprogramming them to a stem cell state, they do not integrate into the genome itself. This method alleviates concerns arising over the potential risks associated with the insertion of foreign DNA to induce reprogramming, which other prior iPS methods use (bottom row in illustration above).

iPS cells are somatic cells (e.g., skin or blood) that have been genetically reprogrammed to a pluripotent stem cell state through forced expression of pluripotency genes.By definition, iPS cells replicate indefinitely and have the potential to differentiate into any cell type in the human body.

Reprogramming factors are the genes introduced into somatic cells that induce a pluripotent stem cell state. Initial reports describing the creation of human iPS cells utilized four reprogramming factors: OCT4, SOX2, KLF4 and MYC (OSKM) (Takahashi, et al. 2007) or OCT4, SOX2, NANOG and LIN28 (OSNL) (Yu, et al. 2007). Subsequent studies revealed that reprogramming using a specific combination of all 6 of these factors combined with SV40LT and a cocktail of small molecules yields iPS cells at much higher efficiency (Yu, et al. 2009; Yu, et al. 2011).

iPS cells are genetically reprogrammed through forced expression of pluripotency genes into somatic cells.The expression of these genes can be accomplished using a variety of different methods.The episomal reprogramming method introduces pluripotency genes into a target cell using circular DNA plasmid vectors (i.e. episomes) that replicate autonomously within the cell cytoplasm and do not integrate into the host cell genome.

Initial methods of iPS cell reprogramming utilized retroviral and lentiviral vectors to introduce pluripotency genes into somatic cells. While these methods generally work well, the viral DNA integrates into the genome of the target cell, and the resulting iPS cells (and cells differentiated from them) will contain foreign DNA, which may result in defects and errors. By contrast, episomal vectors replicate autonomously within the cell cytoplasm and do not integrate into the host genome. In addition, the episomal vectors are released from the target cell at a rate of ~5% per cell cycle resulting in transgene-free or footprint-free iPS cells.These features, combined with recent advancements in episomal reprogramming efficiency, have led to a strong preference for this method to alleviate concerns about genome integrity for drug discovery and cell therapy applications.

Episomal reprogramming has been reported successful from a variety of somatic cells, including fibroblasts, lymphoblastoid cells, and peripheral blood mononuclear cells. Importantly, CDI has optimized its episomal reprogramming method to achieve high efficiency iPS cell generation from small amounts of human peripheral blood. Not only does this enable more streamlined and less invasive collection of donor samples, but ensures increased sterility and lower cost production of iPS cells. In addition, efficient iPS cell production from peripheral blood enables access to large banks of normal and disease-associated clinical samples for disease research and drug screening.

CDIs suite of MyCell Products includes episomal reprogramming of customer-provided donor samples and subsequent genetic engineering and/or differentiation of the iPS cells. In addition, for researchers who would like to generate their own iPS cells, CDIs episomal reprogramming technology is available as a kit from Life Technologies, including Episomal iPSC Reprogramming Vectors, Vitronectin, and Essential 8 Medium. Customer-generated iPS cells using this kit may then be transferred to CDI for genetic engineering and/or differentiation through MyCell Products.

Integration-free iPS cells have been generated using a variety of methods including adenovirus, Sendai virus, piggyBac, minicircle vectors, and direct introduction of protein or synthesized mRNA. The efficiency and success rate of these methods varies depending on the source of somatic cells and experimental conditions, but in general these approaches are limited by impractically low reprogramming efficiency, requirement for higher biosafety containment, and/or labor- and cost-intensive protocols that require repeated transfection/infection.Compared to these methods, episomal reprogramming is virus-free, safe to use, stable, and inexpensive.

A variety of small molecules have been identified that can functionally substitute for one or more reprogramming factors and/or improve the efficiency of iPS cell reprogramming. However, no combination of small molecules has been shown to functionally substitute for all four reprogramming factors. The use of small molecules in iPS cell reprogramming offers some practical advantages including the ability to optimize the chemical structure, fine-tune dose and concentration, and simplify handling and application protocols. However, the use of small molecules presents a number of scientific challenges. Most notably, small molecules may have more than one target, which may or may not be known. In addition, unexpected toxicity and other side effects in vivo may interfere with the clinical application of small molecules.

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CDI | iPS Cells - Cellular Dynamics International

CGI Illustration by Peter Crowther Associates c/o Dbut Art

Andrea Accomazzo: Comet chaser | Suzanne Topalian: Cancer combatant | Radhika Nagpal: Robot-maker | Sheik Humarr Khan: Ebola doctor | David Spergel: Cosmic sceptic | Maryam Mirzakhani: Surface explorer | Pete Frates: Ice-bucket challenger | Koppillil Radhakrishnan: Rocket launcher | Masayo Takahashi: Stem-cell tester | Sjors Scheres: Structure solver | Ones to watch

A former test pilot steered the Rosetta mission to an icy world in deep space. By Elizabeth Gibney

Andreas Reeg/Agentur Focus/Eyevine

Nearly two decades ago, Andrea Accomazzo got into trouble with his girlfriend when she found a scrap of paper on his desk. In his handwriting was scrawled a phone number next to a female name: Rosetta.

She thought it was a girl, says Accomazzo. I had to explain to my jealous Italian girlfriend that Rosetta is an interplanetary mission that is flying to a comet in almost 20 years.

Ever since, Accomazzo has divided his attention. He eventually married his girlfriend and has also spent the past 18 years pursuing the comet 67P/ChuryumovGerasimenko. As flight director for the mission, Accomazzo led the team that steered Rosetta to its August rendezvous with the comet, following a 6.4-billion-kilometre journey from Earth. The pinnacle of the project came in November, when Rosetta successfully set down a lander named Philae, providing scientists with the first data from the surface of a comet and making it one of the most successful missions in the history of the European Space Agency (ESA).

Accomazzo did not act alone: it took a large operations team at ESA to manoeuvre Rosetta with enough precision to drop Philae down just 120 metres from the centre of the landing zone. Given that we'd had a 500-metre error circle, that was not a bad shot, says Fred Jansen, who led the mission. When Philae's anchoring systems failed, the craft bounced into a shady site where it could not charge its solar panels, so the lander lost power after 64 hours. But in that time, it gathered a trove of data that will add to the information collected by Rosetta about the comet's structure and composition. Armed with those insights, scientists hope to better understand the origin and evolution of the Solar System, including whether comets could have brought water and organic molecules to Earth during its infancy.

Accomazzo started off his career focused on a different type of flight. He first trained as a test pilot in the Italian Air Force. But although he loved flying, he found the culture too constraining and after two years he quit to study aerospace engineering. With his quiet, hard-working, sometimes no-nonsense nature, colleagues say that Accomazzo brings a bit of the military with him into mission control.

For Accomazzo, the biggest parallel between flying a fighter jet and Rosetta is the need for split-second judgements. You have to prepare and train a lot to be able to make the right decision, very quickly, he says. Between launch and landing, his team ran 87 full-day simulations.

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365 days: Nature's 10

Major study: Professor Thomas Preiss from ANU JCSMR who has been involved in an international project researching stem cells. Photo: Graham Tidy

Scientists, including some from Canberra, have identified a new type of stem cell which is easier to grow and manipulate as part of a major study detailing the changes cells undergo as they reprogram into stem cells.

Experts from across the globe, including some from the Australian National University John Curtin School of Medical Research, have carried out the most detailed study of how specialised body cells can be reprogrammed to be like cells from the early embryo.

"The ultimate goal with this work is to develop therapies in regenerative medicine which is a therapeutic approach whereby you would ultimately replace cells or tissues or organs that are failing in a patient with replacement parts that are made in a laboratory from the patient's own cells or from genetically highly similar stem cells," Professor Thomas Preiss from ANU's JCSMR said.

Professor Preiss said it was hoped the research could help speed up the development of treatments for many illnesses and conditions.

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"There's a range of diseases where tissues are damaged or cells or lost. It ranges from neurodegenerative disease to spinal cord injuries, stroke, diabetes, blood and kidney diseases and ultimately perhaps even heart disease," he said.

"I'm not saying our publication immediately enables any of these therapies but we're working on the molecular basis of understanding the process of making cells that would be useful for this kind of therapy."

Fifty experts in stem cell biology and genomics technologies have been involved in Project Grandiose which mapped the detailed molecular process involved in the generation of induced pluripotent stem (iPS) cells.

Since the 2012 Nobel Prize winning discovery that body cells can in principle be coaxed to become iPS cells, there has been a surge in research to better understand iPS cell reprogramming.

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Researchers identify stem cells that can be reprogrammed

PUBLIC RELEASE DATE:

26-Nov-2014

Contact: Krista Conger kristac@stanford.edu 650-725-5371 Stanford University Medical Center @sumedicine

Induced pluripotent stem cells made from patients with a form of blistering skin disease can be genetically corrected and used to grow back healthy skin cells in laboratory dishes, researchers at the Stanford University School of Medicine have found. They've termed the new technique "therapeutic reprogramming."

The skin cells formed normal human skin when grafted onto the backs of laboratory mice, they said.

The findings represent a major advance in the battle against the disease, epidermolysis bullosa, in which the top layer of skin, called the epidermis, sloughs off with the slightest friction, leaving open wounds that are difficult to heal. Severely stricken children who survive into their late teens or early 20s often die from invasive squamous cell carcinoma, a skin cancer that can arise during repeated cycles of skin wounding and healing.

"Epidermolysis bullosa is a truly horrible, debilitating skin disease in which the top layer of skin is not properly anchored to the underlying layers," said Anthony Oro, MD, PhD, professor of dermatology. "When they are born, the trauma of birth rips away their skin, and they continue to suffer severe skin wounds that require constant bandaging and medical attention throughout their lives."

Stanford has one of the largest epidermolysis bullosa clinics in the world, with an extremely active and engaged population of patients and their families eager to help researchers. The Stanford Department of Dermatology has been working to find new treatments for the disease for over 20 years. The latest advance, in which researchers replaced the mutated, disease-causing gene in the donor-made induced pluripotent stem cells with a healthy version, was funded by an $11.7 million grant from the California Institute for Regenerative Medicine.

New avenue of treatment

"This treatment approach represents an entirely new paradigm for this disease," Oro said. "Normally, treatment has been confined to surgical approaches to repair damaged skin, or medical approaches to prevent and repair damage. But by replacing the faulty gene with a correct version in stem cells, and then converting those corrected stem cells to keratinocytes, we have the possibility of achieving a permanent fix -- replacing damaged areas with healthy, perfectly matched skin grafts."

Excerpt from:
Blistering skin disease may be treatable with 'therapeutic reprogramming,' researchers say

New York, New York (PRWEB) November 17, 2014

Beyond Batten Disease Foundation (BBDF) and the New York Stem Cell Foundation (NYSCF) have been selected as a national innovator by the Milken Institute and will present their breakthrough findings about juvenile Batten disease at the 6th annual Partnering for Cures, November 16-18 in New York City. The presentation will highlight the collaborative efforts of NYSCF, BBDF and Batten Disease Support and Research Association.

Craig and Charlotte Benson established Beyond Batten Disease Foundation in August 2008 after their then five-year-old daughter, Christiane, was diagnosed with juvenile Batten disease. Together with hundreds of families affected by Batten disease, and many more supporters who share their hope and resolve, they are working tirelessly to create a brighter future for Christiane, and all children with Batten disease.

Watch the Benson Family story:

The Benson Family Story

Beyond Batten Disease and the New York Stem Cell Foundation hope to ramp up funding and partnerships to develop stem cell resources to investigate and explore new treatments and ultimately find a cure for juvenile Batten disease, a fatal illness-affecting children as they convene at the FasterCures, conference. The Washington, D.C.-based center of the Milken Institute will bring together nearly 1,000 medical research leaders, investors and decision-makers to forge the collaborations needed to speed and improve outcomes-driven R&D. NYSCF scientists have created the first iPS cells from a neurological disease and the first ever stem cell disease model from any disease. This discovery was named Time Magazine #1 breakthrough in 2008 because it was the first time anyone has made stem cells from a person with a disease and used them to produce the type of cell that degenerated in that patient. Again, in 2012 Time Magazine recognized the Beyond Batten Disease Foundations creation of a rate genetic disease test as a top ten medical breakthrough.

We know the genetic mutations associated with juvenile Batten disease. This partnership will result in stem cell models of juvenile Batten, giving researchers an unprecedented look at how the disease develops, speeding research towards a cure, said Susan L. Solomon, NYSCF Chief Executive Officer.

Working with NYSCF to generate functional neuronal subtypes from patients and families is a stellar example of one of our key strategies in the fight against juvenile Batten disease: creating resource technology with the potential to transform juvenile Batten disease research and accelerate our timeline to a cure, said Danielle M. Kerkovich, PhD, BBDF Principal Scientist.

Juvenile Batten disease begins in early childhood between the ages of five and ten. Initial symptoms typically begin with progressive vision loss, followed by personality changes, behavioral problems, and slowed learning. These symptoms are followed by a progressive loss of motor functions, eventually resulting in wheelchair use and premature death. Seizures and psychiatric symptoms can develop at any point in the disease.

Juvenile Batten disease is one disorder in a group of rare, fatal, inherited disorders known as Batten disease. Over 40 different errors (mutations) in the CLN3 segment of DNA (gene) have been attributed to juvenile Batten disease. The pathological hallmark of juvenile Batten is a buildup of lipopigment in the bodys tissues. It is not known why lipopigment accumulates or why brain and eventually, heart cells are selectively damaged. It is, however, clear that we need disease-specific tools that reflect human disease in order to figure this out and to build therapy.

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Beyond Batten Disease Foundation and the New York Stem Cell Foundation Chosen as a National Innovator by the Milken ...

Published November 07, 2014

A team of stem cell scientists has identified the biological mechanisms of Parkinsons disease and recreated a model of the disease in a dish.

Researchers at The New York Stem Cell Foundation (NYSCF) Research Institute studied a pair of identical twins one with Parkinsons and one without as well as another unrelated Parkinsons patient and four healthy control subjects to observe key characteristics of the disease. After comparing the individuals biological factors, they noticed differences in the patients neurons ability to produce dopamine. Dopamine production is deficient in Parkinsons disease.

"The unique scenario of identical twins, one with this disease and one without, allowed our scientists an unprecedented look into the mechanisms of Parkinson's disease," Susan L. Solomon, NYSCF chief executive officer, said in a news release. "Advanced stem cell research techniques allow us to push the boundaries of science and see what actually goes wrong at the cellular level, step by step during the disease process."

Parkinsons disease affects an estimated 500,000 people in the United States, according to the National Institutes of Health (NIH). The average age of onset is 60, and the risk of developing it increases with age. Symptoms of Parkinsons include tremor, shaking in the hands, arms, legs, jaw or head; impaired balance or postural instability; slowness of movement; and stiffness of the limbs and trunk.

There is currently no cure for Parkinsons.

While the disease is moderately hereditary, scientists have yet to fully understand the mechanisms of inheritance. The researchers note the DNA mutations that produce the enzyme glucocerebrosidase (GBA) have been linked to a five-fold increased risk of developing Parkinsons, but only 30 percent of people with this mutation have been shown to get the disease by age 80. This suggests that genetic and non-genetic factors cause Parkinsons. In studying the identical twins, scientists were able to analyze these mechanisms.

The scientists made induced pluripotent stem (iPS) cells from skin samples from both twins to generate a cellular model of Parkinsons in a dish, recreating the outstanding features of the disease specifically the dopamine and a-synuclein deficiency.

Scientists saw that the neurons from the twin affected by Parkinsons produced less dopamine and had higher levels of an enzyme called monomine oxidase B (MAO-B), as well as a poorer ability to connect with each other, compared to the twin that did not have the disease.

The findings suggest a possible therapy for Parkinsons: treating neurons with molecules that reduce the activity of MAO-B and GBA, while normalizing -synuclein and dopamine levels.

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Researchers create stem cell model of Parkinsons disease in a dish

45 minutes ago by Nicole Giese Rura

Induced neural stem cells (iNSCs) created from adult cells hold promise for therapeutic transplantation, but their potential in this capacity has been limited by failed efforts to maintain such cells in the desirable multi-potent NSC state without continuous expression of the transcription factors used initially to reprogram them.

Now, Whitehead Institute scientists have created iNSCs that remain in the multi-potent state without ongoing expression of reprogramming factors. This allows the iNSCs to divide repeatedly to generate cells in quantities sufficient for therapy.

"Therapeutically, it's important to make neural stem cells because they can self-renew and make lots of cells," says Whitehead Institute Founding Member Rudolf Jaenisch, who is also a professor of biology at MIT. "If you just make mature neurons, which has been done by others, you never get enough cells."

To make iNSCs via direct lineage conversion researchers use viruses to insert a cocktail of transcription factors into the genome of mouse adult skin cells. A drug triggers these transcription factors to turn on genes active in neural stem cells. This direct conversion, known as transdifferentiation, bypasses the step of pushing the cells first through an embryonic stem-cell-like state.

In previous research, iNSCs remained addicted to the drug and reprogramming transcription factors; if either the drug or the factors was removed, the cells revert to skin cells.

"If the reprogramming factors are still active, it's horrible for the cells," says John Cassady, a scientist in Jaenisch's lab. "The cells would be unable to differentiate and the resulting cells would not be therapeutically useful."

In a paper published online this week in the current issue of the journal Stem Cell Reports, Cassady and other Whitehead scientists describe how they prevented the cells' relapse without keeping the reprogramming factors active. First, the cells were grown in a special medium that selects for neural stem cells. Then, the drug is removed. Instead of reverting into skin cells, the iNSCs remain in a multi-potent state that can differentiate into neurons and glia cells. Cassady also refined the reprogramming cocktail to contain eight transcription factors, which produces iNSCs that are transcriptionally and epigenetically similar to mouse neural stem cells.

Cassady notes that a random sample of skin cells can contain neural precursor cells, which can more easily make the transition to iNSCs. To eliminate the possibility that his method might actually rely on cells having this sort of "head start", Cassady converted fully mature immune system cells called B-lymphocytes, which have a very specific genetic marker, to iNSCs. The resulting cells had the profile of their new identity as iNSCs, yet retained their B-lymphocyte genetic marker, showing that Cassady's method could indeed convert non-neural cells to iNSCs.

Although promising, all of the work to date has been conducted in mouse cells. According to Cassady, researchers should next test this protocol in human cells to see if it can successfully produce the cell populations necessary for therapeutic use.

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Direct generation of neural stem cells could enable transplantation therapy

PUBLIC RELEASE DATE:

6-Nov-2014

Contact: David McKeon dmckeon@nyscf.org 212-365-7440 New York Stem Cell Foundation @nyscf

New York, NY (November 6, 2014) - A team of scientists led by The New York Stem Cell Foundation (NYSCF) Research Institute successfully created a human stem cell disease model of Parkinson's disease in a dish. Studying a pair of identical (monozygotic) twins, one affected and one unaffected with Parkinson's disease, another unrelated Parkinson's patient, and four healthy control subjects, the scientists were able to observe key features of the disease in the laboratory, specifically differences in the patients' neurons' ability to produce dopamine, the molecule that is deficient in Parkinson's disease. In addition, the scientists also identified a potential strategy for developing novel therapies for Parkinson's disease.

Attributed to a combination of genetic and nongenetic factors, Parkinson's disease has no completely effective therapy or cure. Parkinson's disease is moderately heritable, but the mechanisms of this inheritance are not well understood. While genetic forms of the disease exist, sporadic forms are far more common.

"The unique scenario of identical twins, one with this disease and one without, allowed our scientists an unprecedented look into the mechanisms of Parkinson's disease," said Susan L. Solomon, NYSCF Chief Executive Officer. "Advanced stem cell research techniques allow us to push the boundaries of science and see what actually goes wrong at the cellular level, step by step during the disease process."

DNA mutations resulting in the production of a specific enzyme called glucocerebrosidase (GBA) have been linked to a five-fold greater risk of developing Parkinson's disease; however, only 30% of individuals with this mutation have been shown to develop Parkinson's disease by the age of 80. This discordance suggests that multiple factors contribute to the development of Parkinson's disease, including both genetic and non-genetic factors. To date, there has been no appropriate model to identify and test multiple triggers leading to the onset of the disease.

In this study, published today in Cell Reports, a set of identical twins, both with a GBA mutation, provided a unique opportunity to evaluate and dissect the genetic and non-genetic contributions to the development of Parkinson's disease in one twin, and the lack of disease in the other. The scientists made induced pluripotent stem (iPS) cells from skin samples from both twins to generate a cellular model of Parkinson's in a dish, recapitulating key features of the disease, specifically the accumulation of -synuclein and dopamine deficiency.

Upon analyzing the cell models, the scientists found that the dopamine-producing neurons from both twins had reduced GBA enzymatic activity, elevated -synuclein protein levels, and a reduced capacity to synthesize and release dopamine. In comparison to his unaffected brother, the neurons generated from the affected twin produced less dopamine, had higher levels of an enzyme called monoamine oxidase B (MAO-B), and poor ability to connect with each other. Treating the neurons with molecules that lowered the activity of MAO-B together with overexpressed GBA normalized -synuclein and dopamine levels in the cell models. This suggests that a combination therapy for the affected twin may be possible by simultaneously targeting these two enzymes.

"The subject of Parkinson's disease discordant twins gave us an incredible opportunity to utilize stem cell models of disease in a dish to unlock some of the biological mechanisms of disease," said Dr. Scott Noggle, NYSCF Vice President, Stem Cell Research and The NYSCF - Charles Evans Senior Research Fellow for Alzheimer's Disease. "Working with these various different groups and scientists added to the depth and value of the research and we hope our findings will be applicable to other Parkinson's disease patients and other neurodegenerative disorders."

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Scientists create Parkinson's disease in a dish

OpRegen consists of animal product-free retinal pigment epithelial (RPE) cells with high purity and potency that were derived from human embryonic stem cells (hESCs). Cell Cure will conduct the trial in Israel where OpRegen will be transplanted as a single dose into the subretinal space of the eye to test the safety and efficacy of the product. Patient enrollment is expected to begin in 2014 following approval of the trial by the Israel Ministry of Health.

About the OpRegenClinical Trial

Cell Cures Phase I/IIa clinical trial is a dose escalation safety and preliminary efficacy study of hESC-derived Retinal Pigment Epithelial (RPE) cells transplanted subretinally in patients with advanced dry-form AMD called geographic atrophy. The open-label, single center, nonrandomized trial will evaluate three different dose regimens of 50,000 to 500,000 cells. A total of 15 patients will be enrolled. The patients will be 55 years of age and older, with non-neovascular (dry-AMD) who have funduscopic findings of GA in the macula with absence of additional concomitant ocular disorders. The eye most affected by the disease will be treated with the contralateral eye being the control. Following transplantation, the patients will be followed for 12 months at specified intervals, to evaluate the safety and tolerability of OpRegen. A secondary objective of the clinical trial will be to examine the ability of transplanted OpRegen to engraft, survive, and induce changes in visual acuity. In addition to thorough characterization of visual function, a battery of defined ophthalmic imaging modalities will be used to quantify structural changes and rate of GA expansion. The study will be performed at Hadassah Ein Kerem Medical Center in Jerusalem, Israel.

The FDAs acceptance of our IND for the Phase I/IIa trial of OpRegen is a significant milestone for our company, and in the broader development of therapies based on human embryonic stem cells for the treatment of major diseases, said Benjamin Reubinoff, MD, PhD, Chief Scientific Officer of Cell Cure and Chairman of Obstetrics and Gynecology and Director of the Hadassah Human Embryonic Stem Cell Research Center at Hadassah Medical Center, Jerusalem, Israel. We look forward to initiating this first-of-its-kind study, and to continuing the clinical development of OpRegen.

Cell Cures Phase I/IIa study of OpRegen has been designed to provide preliminary, objective functional and structural data on the ability of hESC-RPE cell transplantation to slow the progression of geographic atrophy, in addition to safety data, added Prof. Eyal Banin, Head of the Center for Retinal and Macular Degenerations at the Department of Ophthalmology of Hadassah University Medical Center, Jerusalem, Israel who together with Prof. Reubinoff helped develop this novel treatment over the last decade. We are truly excited that this unique, hESC-based therapy will finally be tested in patients with dry-AMD which severely impacts the quality of life of the elderly, and for which no approved therapy yet exists, Dr. Banin stated.

Information about the trial will be made available at ClinicalTrials.gov website of the National Institutes of Health http://www.clinicaltrials.gov/ct2/home. Additional information will be made available on Cell Cures website at http://www.cellcureneurosciences.com/.

About Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is one of the major diseases of aging and is the leading eye disease responsible for visual impairment of older persons in the US, Europe and Australia. AMD affects the macula, which is the part of the retina responsible for sharp, central vision that is important for facial recognition, reading and driving. There are two forms of AMD. The dry form (dry-AMD) advances slowly and painlessly but may progress to geographic atrophy (GA) in which RPE cells and photoreceptors degenerate and are lost. Once the atrophy involves the fovea (the center of the macula), patients lose their central vision and may develop legal blindness. There are about 1.6 million new cases of dry-AMD in the US annually, and as yet there is no effective treatment for this condition. The yearly economic loss to the gross domestic product in the United States from dry-AMD has been estimated to be $24.4 billion. The market opportunity for a treatment for GA has been estimated at over $5 billion globally. About 10% of patients with dry-AMD develop wet (or neovascular) AMD, the second main form of this disease, which usually manifests acutely and can lead to severe visual loss in a matter of weeks. Wet-AMD can be treated with currently marketed VEGF inhibitors. However, such products typically require frequent repeated injections in the eye, and patients often continue to suffer from continued progression of the underlying dry-AMD disease process. Current annual sales of VEGF inhibitors for the treatment of the wet form of AMD are estimated to be about $7 billion worldwide.

The root cause of the larger problem of dry-AMD is believed to be the dysfunction of RPE cells. Therefore, one of the most exciting new therapeutic strategies for dry-AMD is the transplantation of healthy young RPE cells to support and replace those lost with age. Pluripotent stem cells, such as hESCs, can potentially provide a means of manufacturing such healthy RPE cells on an industrial scale.

About OpRegen

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BioTimes Subsidiary Cell Cure Neurosciences Receives FDA Authorization to Initiate Phase I/IIa Trial of Embryonic ...

Shinya Yamanaka ( , Yamanaka Shin'ya?, born September 4, 1962) is a Japanese Nobel Prize-winning stem cell researcher.[1][2][3] He serves as the director of Center for iPS Cell Research and Application and a professor at the Institute for Frontier Medical Sciences at Kyoto University; as a senior investigator at the UCSF-affiliated J. David Gladstone Institutes in San Francisco, California; and as a professor of anatomy at University of California, San Francisco (UCSF). Yamanaka is also a past president of the International Society for Stem Cell Research (ISSCR).

He received the Wolf Prize in Medicine in 2011 with Rudolf Jaenisch;[6] the Millennium Technology Prize in 2012 together with Linus Torvalds. In 2012 he and John Gurdon were awarded the Nobel Prize for Physiology or Medicine for the discovery that mature cells can be converted to stem cells.[7] In 2013 he was awarded the $3 million Breakthrough Prize in Life Sciences for his work.

Yamanaka was born in Higashisaka Japan in 1962. After graduating from Tennji High School attached to Osaka Kyoiku University,[8] he received his M.D. at Kobe University in 1987 and his PhD at Osaka City University Graduate School in 1993. After this, he went through a residency in orthopedic surgery at National Osaka Hospital and a postdoctoral fellowship at the Gladstone Institute of Cardiovascular Disease, San Francisco.

Afterwards he worked at the Gladstone Institutes in San Francisco, USA and Nara Institute of Science and Technology in Japan. Yamanaka is currently Professor at Kyoto University, where he directs its Center for iPS Research and Application. He is also a senior investigator at the Gladstone Institutes as well as the director of the Center for iPS Cell Research and Application.[9]

Between 1987 and 1989, Yamanaka was a resident in orthopedic surgery at the National Osaka Hospital. His first operation, was removing a benign tumor from his friend Shuichi Hirata, a task he could not complete after one hour, when a skilled surgeon would take ten minutes or so. Some seniors referred to him as "Jamanaka", a pun on the Japanese word for obstacle.[10]

From 1993 to 1996, he was at the Gladstone Institute of Cardiovascular Disease. Between 1996 and 1999, he was an assistant professor at Osaka City University Medical School, but found himself mostly looking after mice in the laboratory, not doing actual research.[10]

His wife advised him to become a practicing doctor, but instead he applied for a position at the Nara Institute of Science and Technology. He stated that he could and would clarify the characteristics of embryonic stem cells, and this can-do attitude won him the job. From 19992003, he was an associate professor there, and started the research that would later win him the 2012 Nobel Prize. He became a full professor and remained at the institute in that position from 20032005. Between 2004 and 2010, Yamanaka was a professor at the Institute for Frontier Medical Sciences.[11] Currently, Yamanaka is the director and a professor at the Center for iPS Cell Research and Application at Kyoto University.

In 2006, he and his team generated induced pluripotent stem cells (iPS cells) from adult mouse fibroblasts.[1] iPS cells closely resemble embryonic stem cells, the in vitro equivalent of the part of the blastocyst (the embryo a few days after fertilization) which grows to become the embryo proper. They could show that his iPS cells were pluripotent, i.e. capable of generating all cell lineages of the body. Later he and his team generated iPS cells from human adult fibroblasts,[2] again as the first group to do so. A key difference from previous attempts by the field was his team's use of multiple transcription factors, instead of transfecting one transcription factor per experiment. They started with 24 transcription factors known to be important in the early embryo, but could in the end reduce it to 4 transcription factors Sox2, Oct4, Klf4 and c-Myc.[1]

Yamanaka practiced judo (2dan black belt) and played rugby as a university student. He also has a history of running marathons. After a 20-year gap, he competed in the inaugural Osaka Marathon in 2011 as a charity runner with a time of 4:29:53. He also took part in the 2012 Kyoto Marathon to raise money for iPS research, finishing in 4:03:19. He also ran in the second Osaka Marathon on November 25, 2012.[12]

In 2007, Yamanaka was recognized as a "Person Who Mattered" in the Time Person of the Year edition of Time Magazine.[13] Yamanaka was also nominated as a 2008 Time 100 Finalist.[14] In June 2010, Yamanaka was awarded the Kyoto Prize for reprogramming adult skin cells to pluripotential precursors. Yamanaka developed the method as an alternative to embryonic stem cells, thus circumventing an approach in which embryos would be destroyed.

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Shinya Yamanaka - Wikipedia, the free encyclopedia