A group of scientists in the US, including an Indian-American from the prestigious Cleveland Clinic, have identified a potential new class of drugs that may prove effective in treating certain common types of blood and bone marrow cancers.

First published in the latest edition of Blood Cancer Discovery, the decade long research which reports that a new pharmacological strategy to preferentially target and eliminate leukemia cells with TET2 mutations, was carried out by Jaroslaw Maciejewski and his collaborator Babal Kant Jha from the Cleveland Clinic Department of Translational Hematology & Oncology Research.

Myeloid leukemias are cancers derived from stem and progenitor cells in the bone marrow that give rise to all normal blood cells.

One of the most common mutations involved in driving myeloid leukemias are found in the TET2 gene, which has been investigated for the last decade by Maciejewski and Jha.

In preclinical models, we found that a synthetic molecule called TETi76 was able to target and kill the mutant cancer cells both in the early phases of disease--what we call clonal hematopoiesis of indeterminate potential, or CHIP--and in fully developed TET2 mutant myeloid leukemia," said Dr Maciejewski.

According to a media release, the research team designed TETi76 to replicate and amplify the effects of a natural molecule called 2HG (2-hydroxyglutarate), which inhibits the enzymatic activity of TET genes.

The TET DNA dioxygenase gene family codes for enzymes that remove chemical groups from DNA molecules, which ultimately changes what genes are expressed and can contribute to the development and spread of disease.

While all members of the TET family are dioxygenases, the most powerful enzymatic activity belongs to TET2, the press release said.

Even when TET2 is mutated, however, its related genes TET1 and TET3 provide residual enzymatic activity.

While significantly less, this activity is still enough to facilitate the spread of mutated cancer cells.

Maciejewski's and Jha's new pharmacologic strategy to selectively eliminate TET2 mutant leukemia cells centers on targeting their reliance on this residual DNA dioxygenase activity, it said.

We took lessons from the natural biological capabilities of 2HG, explained Jha, a principal investigator.

We studied the molecule and rationally designed a novel small molecule, synthesized by our chemistry group headed by James Phillips, PhD. Together, we generated TETi76a similar, but more potent version capable of inhibiting not just TET2, but also the remaining disease-driving enzymatic activity of TET1 and TET3, Jha said.

Cleveland Clinic said that the researchers studied TETi76's effects in both preclinical disease and xenograft models (where human cancer cells are implanted into preclinical models). Additional studies will be critical to investigate the small molecule's cancer-fighting capabilities in patients.

We are optimistic about our results, which show not just that TETi76 preferentially restricts the growth and spread of cells with TET2 mutations, but also gives survival advantage to normal stem and progenitor cells, Jha said.

(Only the headline and picture of this report may have been reworked by the Business Standard staff; the rest of the content is auto-generated from a syndicated feed.)

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Scientists find new class of drugs that may treat blood, bone marrow cancer - Business Standard

Bone Marrow Stem Cells Comments Off on Scientists find new class of drugs that may treat blood, bone marrow cancer – Business Standard | December 26th, 2020

Multiple chimeric antigen receptor (CAR) T-cell therapies for the treatment of lymphomas and multiple myeloma have moved forward in the regulatory process, with 1 new FDA approval in 2020 and others anticipated in the near future.

In July, brexucabtagene autoleucel (Tecartus; KTEX19) received accelerated approval for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) based on the results of the phase 2 ZUMA-2 trial (NCT02601313), bringing the treatment landscape of this hematologic malignancy into a new era.1

This approval is only the very beginning, and we are walking into a sophisticated CAR T-cell therapy era with many constructs being designed with [different mechanisms of action], Michael Wang, MD, said in an interview with Targeted Therapies in Oncology (TTO).

Additional actions by the FDA this year included granting priority review designations to lisocabtagene maraleucel (liso-cel) for the treatment of adult patients with relapsed or refractory (R/R) large B-cell lymphoma, after at least 2 prior therapies,2 as well as to idecabtagene vicleucel (ide-cel; bb2121)as treatment of adult patients with multiple myeloma who have received at least 3 prior therapies, including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an anti-CD38 antibody.3

The approval of brexucabtagene autoleucel, an antiCD19 CAR T-cell product, in MCL was based on objective response rate (ORR) data from patients treated on a single-arm trial who had previously received anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 antibody, and a Bruton tyrosine kinase inhibitor (n = 74).2,4 Eligible patients received leukapheresis and optional bridging therapy, followed by conditioning chemotherapy and a single infusion of brexucabtagene autoleucel 2 106CAR T cells/kg.

The results of ZUMA-2 were published in the New England Journal of Medicine in April and demonstrated a 93% (95% CI, 84%-98%) ORR in 60 response-evaluable patients, 67% (95% CI, 53%-78%) of whom had a complete response (CR). ORRs were consistent across key patient subgroups. Two patients (3%) each had stable and progressive disease.

Progression-free and overall survival (OS) rates at 12 months were 61% and 83%, respectively, and 57% of patients remained in remission at the 12.3-month median follow-up.4 Cytokine release syndrome (CRS) was the most concerning adverse event, occurring in 91% of patients; grade 3 or higher CRS occurred in 15%.

Notably, the patient cohort comprised patients with a median of 3 prior lines of therapy (range, 1-5) and more than half (56%) were considered to have intermediateor high-risk features by the simplified Mantle Cell Lymphoma International Prognostic Index at baseline.

Before CAR T-cell therapy, we did not have any effective means [of getting patients with high-risk MCL into remission]. We used allogeneic transplantation [and] were able to put some of the patients into a long-term remission, but at a heavy price of mortality, said Wang, a professor in the Department of Lymphoma & Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston. Overall, this brings hope to the high-risk patient population. It looks as though fewer patients are relapsing.

Lisocabtagene Maraleucel In February, the FDA granted liso-cel a priority review designation, an action supported by the safety and efficacy findings of the phase 1 TRANSCEND-NHL-001 trial (NCT02631044).2

Histologic subtypes eligible for treatment included diffuse large B-cell lymphoma (DLBCL); high-grade double- or triple-hit B-cell lymphoma; transformed DLBCL from indolent lymphoma; primary mediastinal B-cell lymphoma; and grade 3B follicular lymphoma. Patients were administered 2 sequential infusions of CD8+ and CD4+ CAR T cells following optional bridging therapy and lymphodepleting chemotherapy and were assigned to 1 of 3 target dose levels: 50 106 (1 or 2 doses), 100 106 , or 150 106 CAR-positive T cells. Investigators determined that the recommended target dose was 100 106 CAR-positive T cells.

In the 256 patients who received at least 1 dose of liso-cel and were included in the efficacy-evaluable group, the ORR was 73% (95% CI, 67%-78%), with 53% (95% CI, 47%-59%) achieving a CR. Investigators observed all-grade CRS (42%) and neurological events (30%), but most cases were grade 1 or 2 in severity.

Due to relatively low rates of CRS and neurological events, the administration of liso-cel has been explored in both the inpatient and outpatient settings. One that included a cohort of patients treated in the outpatient setting with proper monitoring versus the traditional inpatient setting demonstrated consistent safety.6

Based on these results, the indication is that you can deliver [liso-cel] in the outpatient setting and the outcomes are good compared with those treated in the inpatient setting, explained study author Carlos R. Bachier, MD, the director of cellular research at Sarah Cannon in Nashville, Tennessee, in an interview with TTO. Aside from that, they also showed that liso-cel could be safely administered outside of university programs and in more community-based programs, most of them being aligned [with] or part of stem cell and bone marrow transplant programs.

The target action date for a decision on the biologics license application (BLA) for liso-cel was extended twice in 2020 and remains under review. In May, the FDA moved the Prescription Drug User Fee Act (PDUFA) goal date out 3 months from its original August deadline.2,7 Bristol Myers Squibb, the company responsible for developing the product, submitted additional information to the agency following the initial BLA submission, which resulted in more review time. Once again, the target action date was pushed in November, this time due to incomplete manufacturing facility inspections resulting from ongoing travel restrictions due to COVID-19. The FDA provided no new action date.8

For patients with multiple myeloma, the B-cell maturation antigen (BCMA)-targeting CAR T-cell therapy idecel is currently under review for approval in patients who have received at least 3 prior therapiesincluding an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an anti-CD38 antibodybased on results of the phase 2 KarMMa trial (NCT03361748).9

Updated trial results were presented at the American Society of Clinical Oncology 2020 Virtual Scientific Program, and showed that both the primary and key secondary end points of ORR and CR rate were 75% and 33%, respectively. The median duration of response was 10.7 months, and the median progression-free survival was 8.8 months in all patients receiving ide-cel. Corresponding medians were 19.0 and 20.2 months among those achieving a CR or stringent CR. The median OS was 19.4 months in all treated patients.

The 128 patients treated received 1 of 3 target dose levels: 150, 300, or 450 106 CAR-positive T cells. The investigators noted that the highest efficacy outcomes were seen in patients in the 450 106 CAR-positive T-cell group, with an ORR of 82% and a 39% CR rate.

The incidence of CRS was 84% across the treatment cohort and increased with higher target doses. Overall, less than 6% of patients have grade 3 or higher CRS and only 1 patient in the highest target dose cohort had a grade 5 event. Neurological toxicity was low across target doses, with no grade 4 or 5 events reported.

At baseline, the majority of patients (51%) had high tumor burden, 39% had extramedullary disease, and 35% had high-risk cytogenetics including deletion 17p or translocations in t(4;14) or t(14;16).

In May, the FDA issued a refusal letter regarding the BLA for ide-cel because the Chemistry, Manufacturing, and Control (CMC) module required more information before they could complete the review.10 In September, the resubmitted application received a priority review and the agency assigned a PDUFA action date of March 27, 2021.11

If approved, ide-cel would be the first CAR T-cell therapy available for the treatment of patients with multiple myeloma.

References:

1. FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. FDA. Updated July 27, 2020. Accessed November 18, 2020. https://bit. ly/3pEDQV5

2. US Food and Drug Administration (FDA) accepts for priority review Bristol-Myers Squibbs biologics license application (BLA) for lisocabtagene maraleucel (liso-cel) for adult patients with relapsed or refractory large B-cell lymphoma. Press release. Bristol Myers Squibb. February 13, 2020. Accessed November 18, 2020. https:// bit.ly/37ruQbs

3. US Food and Drug Administration (FDA) accepts for priority review Bristol Myers Squibb and bluebird bio application for anti-BCMA CAR T cell therapy idecabtagene vicleucel (ide-cel, bb2121). Press release. Bristol Myers Squibb. September 22, 2020. Accessed November 18, 2020. https://bit.ly/3kDhakH

4. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331-1342. doi:10.1056/ NEJMoa1914347

5. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852. doi:10.1016/ S0140-6736(20)31366-0

6. Bachier CR, Palomba ML, Abramson JA, et al. Outpatient treatment with lisocabtagene maraleucel (liso-cel) in 3 ongoing clinical studies in relapsed/refractory (R/R) large B cell non-Hodgkin lymphoma (NHL), including second-line transplant noneligible (TNE) patients: Transcend NHL 001, Outreach, and PILOT. Paper presented at: 2020 Transplantation & Cellular Therapy Meetings; February 19-23, 2020; Orlando, FL. Abstract 29. Accessed November 18, 2020. bit.ly/37I7DC9

7. Bristol Myers Squibb provides update on biologics license application (BLA) for lisocabtagene maraleucel (liso-cel). Press release. Bristol Myers Squibb. May 6, 2020. Accessed November 18, 2020.https://bit.ly/2YFWAs8

8. Bristol Myers Squibb provides regulatory update on lisocabtagene maraleucel (liso-cel). News release. Business Wire. November 16, 2020. Accessed November 18, 2020. https://bwnews.pr/3pKQMZI

9. Bristol Myers Squibb and bluebird bio announce submission of biologics license application (BLA) for anti-BCMA CAR T cell therapy idecabtagene vicleucel (ide-cel, bb2121) to FDA. Press release. Bristol Myers Squibb. March 31, 2020. Accessed November 18, 2020. https://bit.ly/2JwKbxO

10. Bristol Myers Squibb and bluebird bio provide regulatory update on idecabtagene vicleucel (ide-cel, bb2121) for the treatment of patients with multiple myeloma. News release. Business Wire. May 13, 2020.Accessed November 18, 2020. https:// bwnews.pr/3cpgJa1

11. US Food and Drug Administration (FDA) accepts for priority review Bristol Myers Squibb and bluebird bio application for anti-BCMA CAR T cell therapy idecabtagene vicleucel (ide-cel, bb2121). Press release. Bristol Myers Squibb. September 22, 2020. Accessed November 18, 2020. https://bit.ly/3kDhakH

Originally posted here:
CAR T-Cell Therapies Are Set to Expand Into More Hematologic Malignancy Indications - Targeted Oncology

Bone Marrow Stem Cells Comments Off on CAR T-Cell Therapies Are Set to Expand Into More Hematologic Malignancy Indications – Targeted Oncology | December 26th, 2020

New York, Dec. 21, 2020 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Organ and Tissue Transplantation and Alternatives" - https://www.reportlinker.com/p096592/?utm_source=GNW g., kidneys, liver, heart-lung, pancreas, intestines) and the tissue transplantation (e.g., bone, skin, cornea, heart valve) markets, along with the pharmaceuticals that accompany each market.

Also included are experimental xenografts and artificial organs; tissue transplants; and cell transplants (e.g., bone marrow, cord blood, peripheral blood, islet cell). The report touches on the use of fetal cells, stem cells and altered cancer cells.

The arrangement of this report offers an overview of the key elements in the transplantation process: tissue typing, procurement and preservation, immunosuppressants for solid organ and tissue transplants, and postoperative monitoring. International markets are discussed, and information is provided on industry structure and the regulatory environment.

Within each section are discussions of commercialization opportunities for each segment of the market. New or emerging devices, techniques and pharmaceuticals are highlighted.

Profiles of leading companies involved with solid organ transplantation, tissue transplantation, and alternative technologies are included. The report provides information on company placement within the market and strategic analyses of the companies available and emerging products.

An appendix featuring various terms and processes used in transplantation is provided at the end of the report.

This report cites autologous products only in relation to their impact on the market for allografts. It does not include blood products, except for peripheral and umbilical cord blood as a source of stem cells.

By geography, the market has been segmented into the North America, Europe, Asia-Pacific, and Rest of the World regions. Detailed analysis of the market in major countries such as the U.S., Germany, the U.K., Italy, France, Spain, Japan, China, India, Brazil, Mexico, GCC countries and South Africa will be covered in the regional segment. For market estimates, data will be provided for 2019 as the base year, with estimates for 2020 and forecast value for 2024.

Report Includes:- 26 data tables and 37 additional tables- An overview of the global organ and tissue transplantation and alternatives market- Estimation of the market size and analyses of market trends, with data from 2018 to 2019, estimates for 2020 and projection of CAGR through 2024- Details about organ and tissue transplantation and alternatives, their pathophysiology and affects, and major advancement and latest trends- A look at the regulatory scenarios and initiatives by government organization- Analysis of current and future market dynamics and identification of key drivers, restraints and opportunities such as increasing incidence of organ donations, improved awareness about organ donations, side effects of organ and tissue transplantation and antibiotic resistance infections- Coverage of emerging procedures and products in development and discussion on prevalence of major chronic diseases which initiates organ damage or donation- Discussion on the role of the organ procurement organization and information on transplantation process and preparation and coverage of issues like black market donors- Impact analysis of COVID-19 on organ and tissue transplantation and alternatives market- Market share analysis of the key companies of the industry and coverage of events like mergers & acquisitions, joint ventures, collaborations or partnerships, and other key market strategies- Company profiles of major players of the industry, including Abiomed Inc., Bayer AG, F. Hoffmann-La Roche & Co., Johnson & Johnson, Novartis AG, Pfizer Inc. and XVIVO Perfusion

Summary:The global organ and tissue transplantation and alternatives market was valued at REDACTED in 2019.The market is expected to grow at a compound annual growth rate (CAGR) of REDACTED to reach approximately REDACTED by 2024.

Growth of the global market is attributed to factors such as the growing prevalence of obesity, diabetes, cancer, and other chronic diseases which leads to organ damage, a strong product regulatory scenario, and strong investment in research and development activities by key market players including Abbott Laboratories, Cryolife Inc., Bristol-Myers Squibb, Novartis Ag, F. Hoffmann-La Roche Ltd., Medtronic, Arthrex Inc., Depuy Synthes (Johnson & Johnson), and Allosource.

Although various factors facilitate the global market for organ and tissue transplantation and alternatives, certain parameters such as challenges in HLA sequencing and gaps in supply and demand can constrain market growth.For instance, although there is an increasing need for organ transplants, the shortage of organs worldwide limits the number of transplant procedures performed, and in turn creates an impact on transplant diagnostics procedures.

An increasing number of candidates on the waiting list for organ transplant procedures worldwide further widens this gap of availability and requirement of organs for transplant purposes.

Successful organ and tissue transplantation began to arrive in the mid-1970s when tissue typing coupled with the use of cyclosporine provided more successful graft and patient survival. Today, patient and graft survival for kidney transplants is higher than 90% for the first year post-transplant, and often the success rate is 80% to 90% for five years post-transplant, with some recipients living more than 20 years after their transplant.

Continuing developments in organ procurement, organ preservation, tissue typing, and immunosuppressant use have bolstered successful transplantation surgical techniques. Evolving posttransplant drug and testing regimens have added to the success rate with close post-transplant monitoring and immunosuppressant dosage review.Read the full report: https://www.reportlinker.com/p096592/?utm_source=GNW

About ReportlinkerReportLinker is an award-winning market research solution. Reportlinker finds and organizes the latest industry data so you get all the market research you need - instantly, in one place.

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Organ and Tissue Transplantation and Alternatives - GlobeNewswire

Bone Marrow Stem Cells Comments Off on Organ and Tissue Transplantation and Alternatives – GlobeNewswire | December 22nd, 2020

FDAs decision will enable CytoDyn to respond to ongoing requests for leronlimab until Phase 3 trial data is unblinded

VANCOUVER, Washington, Dec. 22, 2020 (GLOBE NEWSWIRE) -- CytoDyn Inc. (OTC.QB: CYDY), (CytoDyn or the Company"), a late-stage biotechnology company developing Vyrologix (leronlimab-PRO 140), a CCR5 antagonist with the potential for multiple therapeutic indications, announced today a treating physician has received authorization from the U.S. Food and Drug Administration (FDA) to administer leronlimab for a COVID-19 patient under emergency IND (eIND).

Nader Pourhassan, Ph.D., President and Chief Executive Officer of CytoDyn, commented, We are very thankful the FDA is allowing severe-to-critical COVID-19 patients access to Vyrologix (leronlimab) again under eIND while we await the unblinding of data from our recently completed Phase 3 registrational trial. We are receiving daily requests from families seeking our drug for a loved one with COVID-19. In recent months, leronlimab received more than 60 eIND authorizations from the FDA, and during the pendency of our COVID-19 trials, we deferred seeking authorizations for eINDs in order to accelerate the pace of enrollment. Now that enrollment has been completed, we are pleased to be able to assist once again and remain hopeful the upcoming results of our Phase 3 trial will enable leronlimab to be more readily available for severe-to-critical COVID-19 patients.

CytoDyns Phase 2b/3 trial to evaluate the efficacy and safety ofleronlimabfor patients with severe-to-critical COVID-19 indications is a two-arm, randomized, double blind, placebo controlled, adaptive design multicenter study. Patients are randomized to receive weekly doses of 700 mg leronlimab, or placebo. Leronlimab and placebo are administered via subcutaneous injection. The study has three phases: Screening Period, Treatment Period, and Follow-Up Period. The primary outcome measured in this study is: all-cause mortality at Day 28. Secondary outcomes measured are: (1) all-cause mortality at Day 14, (2) change in clinical status of subject at Day 14, (3) change in clinical status of subject at Day 28, and (4) change from baseline in Sequential Organ Failure Assessment (SOFA) score at Day 14.

About Coronavirus Disease 2019 CytoDyn completed its Phase 2 clinical trial (CD10) for COVID-19, a double-blinded, randomized clinical trial for mild-to-moderate patients in the U.S. which produced statistically significant results for NEWS2. CytoDyn completed enrollment of 390 patients in its Phase 2b/3 randomized clinical trial for the severe-to-critically ill COVID-19 population and expects to release results in mid-January 2021.

About Leronlimab (PRO 140) The FDA has granted a Fast Track designation to CytoDyn for two potential indications of leronlimab for critical illnesses. The first indication is a combination therapy with HAART for HIV-infected patients and the second is for metastatic triple-negative breast cancer. Leronlimab is an investigational humanized IgG4 mAb that blocks CCR5, a cellular receptor that is important in HIV infection, tumor metastases, and other diseases, including NASH.Leronlimab has completed nine clinical trials in over 800 people and met its primary endpoints in a pivotal Phase 3 trial (leronlimab in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients).

In the setting of HIV/AIDS, leronlimab is a viral-entry inhibitor; it masks CCR5, thus protecting healthy T cells from viral infection by blocking the predominant HIV (R5) subtype from entering those cells. Leronlimab has been the subject of nine clinical trials, each of which demonstrated that leronlimab could significantly reduce or control HIV viral load in humans. The leronlimab antibody appears to be a powerful antiviral agent leading to potentially fewer side effects and less frequent dosing requirements compared with daily drug therapies currently in use.

In the setting of cancer, research has shown that CCR5 may play a role in tumor invasion, metastases, and tumor microenvironment control. Increased CCR5 expression is an indicator of disease status in several cancers. Published studies have shown that blocking CCR5 can reduce tumor metastases in laboratory and animal models of aggressive breast and prostate cancer. Leronlimab reduced human breast cancer metastasis by more than 98% in a murine xenograft model. CytoDyn is, therefore, conducting a Phase 1b/2 human clinical trial in metastatic triple-negative breast cancer and was granted Fast Track designation in May 2019.

The CCR5 receptor appears to play a central role in modulating immune cell trafficking to sites of inflammation. It may be crucial in the development of acute graft-versus-host disease (GvHD) and other inflammatory conditions. Clinical studies by others further support the concept that blocking CCR5 using a chemical inhibitor can reduce the clinical impact of acute GvHD without significantly affecting the engraftment of transplanted bone marrow stem cells.CytoDyn is currently conducting a Phase 2 clinical study with leronlimab to support further the concept that the CCR5 receptor on engrafted cells is critical for the development of acute GvHD, blocking the CCR5 receptor from recognizing specific immune signaling molecules is a viable approach to mitigating acute GvHD. The FDA has granted orphan drug designation to leronlimab for the prevention of GvHD. Due to the lack of patients during the COVID-19 pandemic, the Company is closing down its Phase 2 trial for acute GvHD.

About CytoDyn CytoDyn is a late-stage biotechnology company developing innovative treatments for multiple therapeutic indications based on leronlimab, a novel humanized monoclonal antibody targeting the CCR5 receptor. CCR5 appears to play a critical role in the ability of HIV to enter and infect healthy T-cells. The CCR5 receptor also appears to be implicated in tumor metastasis and immune-mediated illnesses, such as GvHD and NASH.

CytoDyn has successfully completed a Phase 3 pivotal trial with leronlimab in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients. The FDA met telephonically with Company key personnel and its clinical research organization and provided written responses to the Companys questions concerning its recent Biologics License Application (BLA) for this HIV combination therapy in order to expedite the resubmission of its BLA filing for this indication.

CytoDyn has completed a Phase 3 investigative trial with leronlimab as a once-weekly monotherapy for HIV-infected patients. CytoDyn plans to initiate a registration-directed study of leronlimab monotherapy indication. If successful, it could support a label extension. Clinical results to date from multiple trials have shown that leronlimab can significantly reduce viral burden in people infected with HIV. No drug-related serious site injection reactions reported in about 800 patients treated with leronlimab and no drug-related SAEs reported in patients treated with 700 mg dose of leronlimab. Moreover, a Phase 2b clinical trial demonstrated that leronlimab monotherapy can prevent viral escape in HIV-infected patients; some patients on leronlimab monotherapy have remained virally suppressed for more than six years.

CytoDyn is also conducting a Phase 1b/2 clinical trial with leronlimab in metastatic triple-negative breast cancer. More information is at http://www.cytodyn.com.

Forward-Looking StatementsThis press release contains certain forward-looking statements that involve risks, uncertainties and assumptions that are difficult to predict. Words and expressions reflecting optimism, satisfaction or disappointment with current prospects, as well as words such as "believes," "hopes," "intends," "estimates," "expects," "projects," "plans," "anticipates" and variations thereof, or the use of future tense, identify forward-looking statements, but their absence does not mean that a statement is not forward-looking. Forward-looking statements specifically include statements about leronlimab, its ability to have positive health outcomes, the possible results of clinical trials, studies or other programs or ability to continue those programs, the ability to obtain regulatory approval for commercial sales, and the market for actual commercial sales. The Company's forward-looking statements are not guarantees of performance, and actual results could vary materially from those contained in or expressed by such statements due to risks and uncertainties including: (i) the sufficiency of the Company's cash position, (ii) the Company's ability to raise additional capital to fund its operations, (iii) the Company's ability to meet its debt obligations, if any, (iv) the Company's ability to enter into partnership or licensing arrangements with third parties, (v) the Company's ability to identify patients to enroll in its clinical trials in a timely fashion, (vi) the Company's ability to achieve approval of a marketable product, (vii) the design, implementation and conduct of the Company's clinical trials, (viii) the results of the Company's clinical trials, including the possibility of unfavorable clinical trial results, (ix) the market for, and marketability of, any product that is approved, (x) the existence or development of vaccines, drugs, or other treatments that are viewed by medical professionals or patients as superior to the Company's products, (xi) regulatory initiatives, compliance with governmental regulations and the regulatory approval process, (xii) general economic and business conditions, (xiii) changes in foreign, political, and social conditions, and (xiv) various other matters, many of which are beyond the Company's control. The Company urges investors to consider specifically the various risk factors identified in its most recent Form 10-K, and any risk factors or cautionary statements included in any subsequent Form 10-Q or Form 8-K, filed with the Securities and Exchange Commission. Except as required by law, the Company does not undertake any responsibility to update any forward-looking statements to take into account events or circumstances that occur after the date of this press release.

CONTACTSInvestors: Michael MulhollandOffice: 360.980.8524, ext. 102mmulholland@cytodyn.com

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FDA Resumes eIND Approval for Severe-to-Critical COVID-19 Patients Use of Vyrologix (leronlimab) Following Full Enrollment in CytoDyn's Phase 3 Trial...

Bone Marrow Stem Cells Comments Off on FDA Resumes eIND Approval for Severe-to-Critical COVID-19 Patients Use of Vyrologix (leronlimab) Following Full Enrollment in CytoDyn’s Phase 3 Trial… | December 22nd, 2020

MSPhotographic/Getty Images

Most kids with peanut allergies do not outgrow them. But, with a little help, some might be able to better tolerate accidental exposures.

In January, the Food and Drug Administration approved Palforzia, a new drug designed to help kids who are allergic to peanuts react better, if they are accidentally exposed.

"Because there is no cure, allergic individuals must strictly avoid exposure to prevent severe and potentially life-threatening reactions," Dr. Peter Marks, director of the FDA's Center for Biologics Evaluation and Research said at the time in a news release. "When used in conjunction with peanut avoidance, Palforzia provides an FDA-approved treatment option to help reduce the risk of these allergic reactions."

Palforzia is not designed to be administered during an allergic reaction, instead it works as an allergy exposure therapy: children ages 4 through 17 receive daily doses of peanut powder under clinical supervision, and slowly up-dose it over time.

In clinical trials, the strategy worked well, but not perfectly. When peanut-allergic kids were fed 600 milligrams of peanut protein, 67.2% of Palforzia recipients who'd been using the medication for six months tolerated it, while only 4% of the control group did.

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The 11 most mind-blowing, awe-inspiring health discoveries and innovations of 2020 - Business Insider - Business Insider

Bone Marrow Stem Cells Comments Off on The 11 most mind-blowing, awe-inspiring health discoveries and innovations of 2020 – Business Insider – Business Insider | December 22nd, 2020

First gene therapy to receivefull EU marketing authorization for eligible MLD patients

One-time treatment with Libmeldy has been shown to preserve motor and cognitive function

Achievement shared with research alliance partners Fondazione Telethon and Ospedale San Raffaele

BOSTON and LONDON and MILAN, Italy, Dec. 21, 2020 (GLOBE NEWSWIRE) -- Orchard Therapeutics (Nasdaq: ORTX), a global gene therapy leader, and its research alliance partners Fondazione Telethon and Ospedale San Raffaele, today announced that the European Commission (EC) granted full (standard) market authorization for Libmeldy (autologous CD34+ cells encoding the ARSA gene), a lentiviral vector-based gene therapy approved for the treatment of metachromatic leukodystrophy (MLD), characterized by biallelic mutations in theARSAgene leading to a reduction of the ARSA enzymatic activity in children with i) late infantile or early juvenile forms, without clinical manifestations of the disease, or ii) the early juvenile form, with early clinical manifestations of the disease, who still have the ability to walk independently and before the onset of cognitive decline. Libmeldy is the first therapy approved for eligible patients with early-onset MLD.

MLD is a very rare, fatal genetic disorder caused by mutations in the ARSA gene which lead to neurological damage and developmental regression. In its most severe and common forms, young children rapidly lose the ability to walk, talk and interact with the world around them, and most pass away before adolescence. Libmeldy is designed as a one-time therapy that aims to correct the underlying genetic cause of MLD, offering eligible young patients the potential for long-term positive effects on cognitive development and maintenance of motor function at ages at which untreated patients show severe motor and cognitive impairments.

Todays EC approval of Libmeldy opens up tremendous new possibilities for eligible MLD children faced with this devastating disease where previously no approved treatment options existed, said Bobby Gaspar, M.D., Ph.D., chief executive officer of Orchard. Libmeldy is Orchards first product approval as a company, and I am extremely proud of the entire team who helped achieve this milestone. We are grateful for and humbled by the opportunity to bring this remarkable innovation to young eligible patients in the EU.

With Libmeldy, a patients own hematopoietic stem cells (HSCs) are selected, and functional copies of the ARSA gene are inserted into the genome of the HSCs using a self-inactivating (SIN) lentiviral vector before these genetically modified cells are infused back into the patient. The ability of the gene-corrected HSCs to migrate across the blood-brain barrier into the brain, engraft, and express the functional enzyme has the potential to persistently correct the underlying disease with a single treatment.

The EC approval of Libmeldy comes more than a decade after the first patient was treated in clinical trials performed at our Institute, and ushers in a remarkable and long-awaited shift in the treatment landscape for eligible MLD patients, said Luigi Naldini, M.D, Ph.D., director of the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy. Our team at SR-Tiget has been instrumental in advancing the discovery and early-stage research of this potentially transformative therapy to clinical trials in support of its registration through more than 15 years of studies supported by Fondazione Telethon and Ospedale San Raffaele, and we are extremely proud of this achievement and what it means for patients and the field of HSC gene therapy.

MLD is a heart-breaking disease that causes immeasurable suffering and robs children of the chance of life, said Georgina Morton, chairperson of ArchAngel MLD Trust. As a community, we have been desperate for a treatment for young MLD patients, and we are incredibly excited to now have such a ground-breaking option approved in the EU.

The marketing authorization for Libmeldy is valid in all 27 member states of the EU as well as the UK, Iceland, Liechtenstein and Norway. Orchard is currently undertaking EU launch preparations related to commercial drug manufacturing, treatment site qualification and market access.

Data Supporting the Clinical and Safety Profile of Libmeldy

The marketing authorization for Libmeldy is supported by clinical studies in both pre- and early- symptomatic, early-onset MLD patients performed at the SR-Tiget. Early-onset MLD encompasses the disease variants often referred to as late infantile (LI) and early juvenile (EJ). Clinical efficacy was based on the integrated data analysis from 29 patients with early-onset MLD who were treated with Libmeldy prepared as a fresh (non-cryopreserved) formulation. Results of this analysis indicate that a single-dose intravenous administration of Libmeldy is effective in modifying the disease course of early-onset MLD in most patients.

Clinical safety was evaluated in 35 patients with MLD (the 29 patients from the integrated efficacy analysis as well as six additional patients treated with the cryopreserved formulation of Libmeldy). Safety data indicate that Libmeldy was generally well-tolerated. The most common adverse reaction attributed to treatment with Libmeldy was the occurrence of anti-ARSA antibodies (AAA) reported in five out of 35 patients. Antibody titers in all five patients were generally low and no negative effects were observed in post-treatment ARSA activity in the peripheral blood or bone marrow cellular subpopulations, nor in the ARSA activity within the cerebrospinal fluid. In addition to the risks associated with the gene therapy, treatment with Libmeldy is preceded by other medical interventions, namely bone marrow harvest or peripheral blood mobilization and apheresis, followed by myeloablative conditioning, which carry their own risks. During the clinical studies, the safety profiles of these interventions were consistent with their known safety and tolerability.

For further details, please see the Summary of Product Characteristics (SmPC).

About MLD and Libmeldy

MLD is a rare and life-threatening inherited disease of the bodys metabolic system occurring in approximately one in every 100,000 live births. MLD is caused by a mutation in the arylsulfatase-A (ARSA) gene that results in the accumulation of sulfatides in the brain and other areas of the body, including the liver, gallbladder, kidneys, and/or spleen. Over time, the nervous system is damaged, leading to neurological problems such as motor, behavioral and cognitive regression, severe spasticity and seizures. Patients with MLD gradually lose the ability to move, talk, swallow, eat and see. In its late infantile form, mortality at five years from onset is estimated at 50% and 44% at 10 years for juvenile patients.1

Libmeldy (autologous CD34+ cell enriched population that contains hematopoietic stem and progenitor cells (HSPC) transduced ex vivo using a lentiviral vector encoding the human arylsulfatase-A (ARSA) gene), also known as OTL-200, is approved in the European Union for the treatment of MLD in eligible early-onset patients. In the U.S., OTL-200 is an investigational therapy which has not been approved by the U.S. Food and Drug Administration (FDA) for any use. Libmeldy was acquired from GSK in April 2018 and originated from a pioneering collaboration between GSK and the Hospital San Raffaele and Fondazione Telethon, acting through their joint San Raffaele-Telethon Institute for Gene Therapy in Milan, initiated in 2010.

About Orchard

Orchard Therapeutics is a global gene therapy leader dedicated to transforming the lives of people affected by rare diseases through the development of innovative, potentially curative gene therapies. Our ex vivo autologous gene therapy approach harnesses the power of genetically modified blood stem cells and seeks to correct the underlying cause of disease in a single administration. In 2018, Orchard acquired GSKs rare disease gene therapy portfolio, which originated from a pioneering collaboration between GSK and the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy. Orchard now has one of the deepest and most advanced gene therapy product candidate pipelines in the industry spanning multiple therapeutic areas where the disease burden on children, families and caregivers is immense and current treatment options are limited or do not exist.

Orchard has its global headquarters inLondonandU.S.headquarters inBoston. For more information, please visitwww.orchard-tx.com, and follow us on Twitter and LinkedIn.

Availability of Other Information About Orchard

Investors and others should note that Orchard communicates with its investors and the public using the company website (www.orchard-tx.com), the investor relations website (ir.orchard-tx.com), and on social media (Twitter andLinkedIn), including but not limited to investor presentations and investor fact sheets,U.S. Securities and Exchange Commissionfilings, press releases, public conference calls and webcasts. The information that Orchard posts on these channels and websites could be deemed to be material information. As a result, Orchard encourages investors, the media, and others interested in Orchard to review the information that is posted on these channels, including the investor relations website, on a regular basis. This list of channels may be updated from time to time on Orchards investor relations website and may include additional social media channels. The contents of Orchards website or these channels, or any other website that may be accessed from its website or these channels, shall not be deemed incorporated by reference in any filing under the Securities Act of 1933.

About Fondazione Telethon, Ospedale San Raffaele and the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget)

Based in Milan, Italy, the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) is a joint venture between the Ospedale San Raffaele, a clinical-research-university hospital established in 1971 to provide international-level specialized care for the most complex and difficult health conditions, and Fondazione Telethon, an Italian biomedical charity born in 1990 and focused on rare genetic diseases. SR-Tiget was established in 1995 to perform research on gene transfer and cell transplantation and translate its results into clinical applications of gene and cell therapies for different genetic diseases. Over the years, the Institute hasgiven a pioneering contribution to the field with relevant discoveries in vector design, gene transfer strategies, stem cell biology, identity and mechanism of action of innate immune cells. SR-Tiget has also established the resources and framework for translating these advances into novel experimental therapies and has implemented several successful gene therapy clinical trials for inherited immunodeficiencies, blood and storage disorders, which have already treated >115 patients and have led through collaboration with industrial partners to the filing and approval of novel advanced gene therapy medicines.

For more information:

Forward-Looking Statements

This press release contains certain forward-looking statements about Orchards strategy, future plans and prospects, which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements may be identified by words such as anticipates, believes, expects, plans, intends, projects, and future or similar expressions that are intended to identify forward-looking statements. Forward-looking statements include express or implied statements relating to, among other things, Orchards business strategy and goals, including its plans and expectations for the commercialization of Libmeldy, and the therapeutic potential of Libmeldy, including the potential implications of clinical data for eligible patients. These statements are neither promises nor guarantees and are subject to a variety of risks and uncertainties, many of which are beyond Orchards control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. In particular, these risks and uncertainties include, without limitation:: the risk that prior results, such as signals of safety, activity or durability of effect, observed from clinical trials of Libmeldy will not continue or be repeated in our ongoing or planned clinical trials of Libmeldy, will be insufficient to support regulatory submissions or marketing approval in the US or to maintain marketing approval in the EU, or that long-term adverse safety findings may be discovered; the inability or risk of delays in Orchards ability to commercialize Libmeldy, including the risk that we may not secure adequate pricing or reimbursement to support continued development or commercialization of Libmeldy; the risk that the market opportunity for Libmeldy, or any of Orchards product candidates, may be lower than estimated; and the severity of the impact of the COVID-19 pandemic on Orchards business, including on clinical development, its supply chain and commercial programs. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements.

Other risks and uncertainties faced by Orchard include those identified under the heading "Risk Factors" in Orchards quarterly report on Form 10-Q for the quarter endedSeptember 30, 2020, as filed with theU.S. Securities and Exchange Commission(SEC), as well as subsequent filings and reports filed with theSEC. The forward-looking statements contained in this press release reflect Orchards views as of the date hereof, and Orchard does not assume and specifically disclaims any obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law.

Contacts

InvestorsRenee LeckDirector, Investor Relations+1 862-242-0764Renee.Leck@orchard-tx.com

MediaChristine HarrisonVice President, Corporate Affairs+1 202-415-0137media@orchard-tx.com

1 Mahmood et al. Metachromatic Leukodystrophy: A Case of Triplets with the Late Infantile Variant and a Systematic Review of the Literature.Journal of Child Neurology2010, DOI:http://doi.org/10.1177/0883073809341669

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Orchard Therapeutics Receives EC Approval for Libmeldy for the Treatment of Early-Onset Metachromatic Leukodystrophy (MLD) - GlobeNewswire

Bone Marrow Stem Cells Comments Off on Orchard Therapeutics Receives EC Approval for Libmeldy for the Treatment of Early-Onset Metachromatic Leukodystrophy (MLD) – GlobeNewswire | December 22nd, 2020

Autologous bone marrow mononuclear cell (BMMNC) transplantation has been widely studied in recent years. The fresh cell cocktail in BMMNCs, without going through the in vitro culture process, helps to establish a stable microenvironment for osteogenesis, and each cell type may play a unique role in bone regeneration. Our study compared the efficacy of concentrated fresh BMMNCs and cultured bone marrow-derived mesenchymal stem cells (BMSCs) in Beagle dogs for the first time. Fifteen-millimeter segmental bone defects were created in the animals tibia bones. In BMMNCs group, the defects were repaired with concentrated fresh BMMNCs combined with -TCP (n = 5); in cultured BMSC group, with in vitro cultured and osteo-induced BMSCs combined with -TCP (n = 5); in scaffold-only group, with a -TCP graft alone (n = 5); and in blank group, nothing was grafted (n = 3). The healing process was monitored by X-rays and single photon emission computed tomography. The animals were sacrificed 12months after surgery and their tibias were harvested and analyzed by microcomputed tomography and hard tissue histology. Moreover, the microstructure, chemical components, and microbiomechanical properties of the regenerated bone tissue were explored by multiphoton microscopy, Raman spectroscopy and nanoindentation. The results showed that BMMNCs group promoted much more bone regeneration than cultured BMSC group. The grafts in BMMNCs group were better mineralized, and they had collagen arrangement and microbiomechanical properties similar to the contralateral native tibia bone. These results indicate that concentrated fresh bone marrow mononuclear cells may be superior to in vitro expanded stem cells in segmental bone defect repair. 2020 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals LLC on behalf of AlphaMed Press.

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One of the astonishing aspects of the human response to the COVID-19 pandemic has been how quickly scientists pivoted to studying every facet of the virus in order to mitigate the loss of life and plan for a return to normalcy. At the same time, a lot of non-coronavirus research ground to a near halt.

With research labs and offices shuttered for all but essential workers, many scientists were stuck at home, their fieldwork and meetings canceled and planned experiments kicked down the road as they struggled to figure out how to keep their research programs going. Many took the opportunity to catch up on writing grants and papers; some in between caring for kids came up with strategic workarounds to keep the scientific juices flowing.

To gauge how researchers in different fields are managing,Knowable Magazine spoke with an array of scientists and technical staff among them a specialist keeping alive genetically important strains of fruit flies, the maintenance chief of an astronomical observatory working to keep telescopes safe and on standby during the lockdown, and a paediatrician struggling to manage clinical trials for a rare genetic disease. Here are a few slices of scientific life during the pandemic.

Agnieszka Czechowicz, Stanford University School of Medicine

Czechowicz is a paediatrician in Stanfords division of stem cell transplantation and regenerative medicine, where she manages a research group that develops new therapies and conducts clinical trials on rare genetic diseases.

Agnieszka Czechowiczs father suffers from severe Parkinsons disease. The coronavirus pandemic forced him to remain indoors and away from people, robbing him of the physical conditioning and social interactions he needs to cope with his disease. A recent fall left him in the hospital, bringing the additional worry that he might contract COVID-19 there and isolating him further.

For Czechowicz, his situation brought into sharp relief the challenges the coronavirus has forced upon those carrying out clinical trials, including those she is running, which involve patients traveling to hospitals around the country. Would I have him travel to any clinical site right now for a new Parkinsons treatment? she says. Absolutely not.

The pandemic forced Czechowicz to halt clinical trials she oversees for a rare genetic disease of children called Fanconi anAemia, a condition that impairs the bodys ability to repair damaged DNA and often leads to bone marrow failure and cancer. The treatment Czechowicz and colleagues are testing involves extracting blood-forming stem cells from the patients bone marrow, inserting a healthy copy of a missing or malfunctioning gene and then reinfusing those cells back into the patient.

Every aspect of what I do is massively impacted by the pandemic, Czechowicz says. One of her early-stage clinical trials involves testing the safety of the therapy. But during the initial shutdown which started in mid-March and lasted for two months her patients could not readily travel to Stanford for the necessary follow-up visits, and remote monitoring was difficult.

Theres special blood testing and bone marrow testing that we need to do. In particular, its critical to get the samples to make sure the patients, for example, arent developing leukAemia, she says. Theres no way to know that without really checking the bone marrow. She had to clear large hurdles to get her patients evaluated.

Another early-stage trial, designed to determine the effectiveness of the therapy, also had to stop enrolling new patients. Because speed is important when it comes to treating Fanconi anaemia the children are likely losing stem cells all the time any delay in treatment can be a source of great anxiety for their parents. Czechowicz had to explain to them why the trials were temporarily halted. It was really challenging to have these discussions with the families, she says.

With the easing of travel and workplace restrictions, the families began traveling to Stanford in June but with infections back on the rise, many families are becoming hesitant again, says Czechowicz. Fortunately, her trials are small, so she can guide each family through the process of safely resuming the trials and continuing with follow-up. Her own team also has to follow strict safety protocols. For example, even though her lab has 10 members, only two can be in the lab at any one time, and only one parent is allowed into the clinic with the child.

Not all clinical trials can pay such close attention to individual patients. Large trials with hundreds of patients can involve multiple sites and require much more monitoring, so resuming those remains difficult. Also, restrictions on working full bore are slowing the pipeline for new therapies. The impact of that, were not going to see for many years to come, Czechowicz says.

Abolhassan Jawahery, University of Maryland, College Park

Jawahery is a particle physicist and a member of LHCb, one of the main experiments at the Large Hadron Collider (LHC) at CERN, the particle physics laboratory near Geneva.

In December 2018, well before the coronavirus pandemic began, the LHC shut down for upgrades. Housed in a 27-kilometre-long tunnel about 100 meters underground, the LHC accelerates two beams of protons, one clockwise and one counterclockwise, and makes them collide head-on at four locations. There, four gigantic subterranean detectors ATLAS, CMS, LHCb and ALICE sift through the debris of particles created by the collisions, looking for evidence of new physics. (For example, ATLAS and CMS found the Higgs boson, the fundamental particle of the Higgs field, which gives all elementary particles their mass.)

For its next set of experiments, which aim to probe the properties of subatomic particles with greater precision, the LHC needed to increase the intensity of its proton beams. Consequently, the four detectors needed to be upgraded too, to handle the resultant higher temperatures and increased radiation at the sites of the particle collisions. The work was on track for a restart around May 2021 until the pandemic swept all the scientists careful plans away.

The LHC and its four detectors are each run by a separate collaboration. CERN, which manages the LHC, is hopeful it can restart the collider by February 2022. They think that they can get the accelerator going if there are no more major catastrophic events, says physicist Abolhassan Jawahery. But the impact on the four detectors is less clear.

For the LHCb upgrade, Jawaherys team at the University of Maryland had been working on building about 4,000 extremely sensitive electronic circuit boards. These boards have to be burned in before they can be sent to CERN. We put them in an oven, literally cooking the boards and then running extensive tests in order to get them ready so that we can put them in the accelerator and run them for 10 to 20 years, says Jawahery. And none of that could be done during the pandemic shutdown.

The team resumed its work in June, but with restrictions put in place by the state of Maryland. Jawahery runs two labs, and for months was allowed only two people at a time in one lab and three in the other, making progress extremely slow. Still, his team is fortunate that it does not depend on supplies from countries hit hard by the coronavirus. Other labs werent so lucky. Scientists in Milan, for example, built some electronics and detector components for the LHCb, and a lab at Syracuse University in New York built sensors that relied on shipments from Milan. When Milan was completely closed down at the height of the pandemic, Syracuse, too, stopped working on Milan-dependent components.

For Jawahery the lockdown had a silver lining. The LHCs most recent run had produced about 25 gigabytes of data per second but his team had found little time to analyse any of it before the pandemic. We were complaining that we were spending all our time building the new instrument and the data keeps on coming, he says. When he and his team were locked out of their labs, they turned to their data backlog. We could do actual physics, he says. We are already getting ready to publish some papers.

Gordon Gray, Princeton University

Gray is a professionalDrosophila specialist in the department of molecular biology.

Gordon Gray has been called the chef de cuisine of Princetons fly kitchen, where he has been feeding flies for 46 years. He concocts meals for millions of fruit flies, at least 150 litres each week. When the pandemic hit in March and universities around the world shut down, Princeton deemed Grays work an essential service: The Drosophilafruit flies could not be allowed to die off.

Princetons flies include mutant and transgenic strains everything from ones that allow researchers to study the genes that influence normal development of a fly embryos organs, to those that have cancer-causing mutations. If the flies starved, researchers would need months or years to recreate these strains, says Princeton molecular biologist Elizabeth Gavis. And often, as techniques in molecular biology improve, the biologists reexamine flies they had studied earlier to get a more fine-grained understanding, making it worthwhile to preserve the strains.

Normally, if a lab had to shut down, researchers would send their flies to stock centres, such as one at Bowling Green State University in Ohio, that preserve the flies as part of their genetic library. But the stock centres couldnt handle Princetons flies, so Gray found himself on his own. Its basically catch as catch can with regards to the various labs here, just to keep things operational, he says.

For months, university pandemic restrictions have allowed only one person to be in Grays kitchen at a time. This has caused problems. Before the pandemic began, Gray, who is in his late 60s, had started training someone as a backup. But because of the one-person restriction, Gray and his trainee havent been able to work together. Gray envisions doing so soon, while wearing masks, keeping nearly 12 feet apart and communicating using hand signals.

To whip up a batch of fly food, or media, Gray uses a 50-litre steel cauldron, to which is attached a mixer that looks like an outboard motor. Gray fills the cauldron with water and adds agar, sugars, yeasts, salts and cornmeal, then brings it to a boil, all the while stirring watchfully. You dont want it to boil over, because when it does you wind up with a gigantic pancake on the floor, which you have to scoop up immediately because it gels, he says. Once the suspension cools to the right temperature, Gray adds an acid to inhibit mould, then dispenses precise amounts of the media into bottles and vials.

Even before the pandemic, Grays kitchen was isolated, to keep errant fruit flies from contaminating the pristine media. But at least he could work regular hours, because he knew the rhythms of the 10 or so fly labs he cooked for. That has changed. Labs, restricted to two occupants at a time, are now working seven days a week on rotating shifts. Gray comes in to work at all hours, because he cannot predict when each batch of fly food will run out and hell need to cook more.

He tries to work mostly at night to avoid coming into contact with others. But he still worries for his health, given his asthma and age-related risk. The relentless pandemic is taking a toll. Its exhausting, he says. It doesnt help not knowing when we will return to a sense of normalcy.

Celeste Kidd, University of California, Berkeley

Kidd is a child developmental psychologist who uses behavioural tests and computational methods to understand how children acquire knowledge.

When UC Berkeley locked down in March, Celeste Kidd found herself closeted at home, dealing simultaneously with virtual meetings and her three-year-old son. During the early days of the pandemic, Kidd kept a supply of treats handy, and when her toddler came up to her during a meeting shed sneak him some under the desk. But she hadnt accounted for how long the pandemic would last. It turns out thats not a good strategy, long term, she says. I was very literally rewarding him for bad behaviour.

Kidds son soon learned that acting up during her meetings meant more candy. I knew that would happen. I did it anyway because I didnt have the bandwidth to come up with a better solution, she says. But Kidd knew from her own research that children are also extremely flexible and can unlearn behaviours. Eventually, she had a chat with her son. First, she admitted to him that she had made a mistake by giving him candy when he disrupted her meetings, and that was bad of her. Then she brought in new rules: no candy for misbehaving and misbehaviour could even mean no treats for the rest of day. We had some meltdown moments, says Kidd. But he gets it now and he doesnt do those things.

Her son may be the only child Kidd gets to interact with during the pandemic. Thats a huge loss for her research, because the bulk of her work focuses on young children. In normal times, families would bring their children to her lab, where her research team would track their gaze as they watched videos. In one study, for example, infants about seven to nine months old would look away (demonstrating lack of interest) when the events in the video were either too complex or too simple, suggesting that infants use their cognitive resources for stimuli that have just the right amount of information.

Such work, of course, requires the presence of parent, child and researchers, all in the same room. None of that is going to happen anytime soon, she says. Those families are not going to feel comfortable coming in for a while.

Kidd is also concerned about the impact of the pandemic on younger scientists. One of her undergraduate students had spent six months working on a study aimed at exploring the complexity of kids play patterns using physical objects and their relation to working memory and other cognitive resources. The university had approved the protocol, but shelter-in-place orders went into effect the week the first child was to come for the experiment. I feel so bad for her as a young scientist, to have done all this hard work and then right when you get to the fun part, which is collecting the data and finding out if her ideas have lasting merit, she doesnt get to do that part, Kidd says.

The situation might be even worse for grad students and postdocs. All of them are experiencing a big blow to morale in general, because there is so much uncertainty about what the future holds, she says. University budget cuts mean fewer slots for graduate students and fewer jobs for postdocs. Its very hard to stay motivated and get things done when youre not sure if there will be a payoff in the future, says Kidd. Thats literally a study that we ran in the lab so were all acutely aware of it.

Maxime Boccas, ESO Paranal Observatory

Boccas is the head of maintenance, support and engineering at the European Southern Observatorys Paranal Observatory in Chile.

When the massive domes of the Very Large Telescope, a constellation of four 8-meter-class telescopes atop Mount Paranal in Chiles Atacama Desert, open to the night sky each evening and the telescopes get ready for observations, its like a dragon waking up.

When the pandemic hit in March, the dragon on Mount Paranal closed its eyes to the cosmos and slept the first shutdown in its 20-year history, which included a major earthquake in 2010 that paralyzed much of the rest of Chile. For those who had to leave Paranal, it was like being sent away from home. We spend 40% of our life here, says Maxime Boccas, who oversaw the process of ensuring an orderly shutdown of the sites scientific and technical facilities. We work and sleep here, and we stay here eight days in a row. Some of Boccass colleagues have been doing that for 20 to 25 years. Leaving Paranal was like leaving their second home. That was a weird feeling.

The skeleton staff just 20 of the normal 150 or so people remained on site kept the observatory safe, ensuring that essential systems continued working: computers that astronomers were accessing remotely, the fire detection system and the earthquake protection system essential for protecting the 8-meter-wide primary mirrors from Chiles frequent quakes. The mirrors will likely never be made again, says Boccas. All the factories that cast and polished them are dismantled. If we lost a mirror, it would take between 5 and 10 years to build up the factory again and fabricate it. So each mirror has an airbag a tube that inflates around it when the system detects tremors and other protections.

During the shutdown, astronomers kept their fingers crossed. They were anxious that no big thing, like a supernova in our galaxy, would explode, Boccas says. The heavens have been quiet, but the six-month shutdown harmed research that involves continuously monitoring the same patch of the sky for transient phenomena such as gamma ray bursts. It creates a hole in their science program, says Boccas.

The observatory began a slow return to normalcy on September 9. Boccas is overseeing the reawakening of each telescope, one at a time. The staff still less than full strength is now working in shifts that have doubled from 8 to 15 days to limit the amount of travel to and from the site. The four large telescopes are now up and running again, and Boccas hopes they will be back to working together as one by the end of January.

Boccas, his crew and a few lucky astronomers are glad to be back at Paranal. It really feels like a family and I think everyone has noticed that, he says. Even in the kitchen, they have to cook for 30 people instead of 150, so the quality of the food is different, its slightly better.

But even as people return to the observatory, Boccas worries about long-term effects of the shutdown. Given the reduced staff, he has had to cut down on the frequency of preventive maintenance tasks, such as changing belts and lubricating motors, potentially shortening the lifetime of some components. We will not know until six months, a year or three years from now, he says.

This article is part ofReset: The Science of Crisis & Recovery, an ongoing series exploring how the world is navigating the coronavirus pandemic, its consequences and the way forward. Reset is supported by a grant from the Alfred P. Sloan Foundation.

Anil Ananthaswamy is a science journalist who enjoys writing about cosmology, consciousness and climate change. Hes a 2019-20 MIT Knight Science Journalism fellow. His latest book is Through Two Doors at Once. http://www.anilananthaswamy.com.

This article originally appeared in Knowable Magazine, an independent journalistic endeavour from Annual Reviews.

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How Researchers Are Making Do in the Time of COVID-19 - The Wire Science

Bone Marrow Stem Cells Comments Off on How Researchers Are Making Do in the Time of COVID-19 – The Wire Science | December 21st, 2020

Problems soon after transplant

Many of the problems that can happen shortly after the transplant come from having the bone marrow wiped out by medicines or radiation just before the transplant. Others may be side effects of the conditioning treatments themselves.

Your transplant team can help you cope with side effects. Some can be prevented, and most can be treated to help you feel better.This is not a complete list and you should tell your doctor or transplant team about any problems you have or changes you notice. Some of these problems can be life-threatening, so its important to be able to reach your doctor or transplant team at night, on weekends, and during holidays. Ask for their after hours contact numbers to makesure you will be able to do this.

Mucositis (inflammation or sores in the mouth) is a short-term side effect that can happen with chemo and radiation. It usually gets better within a few weeks after treatment, but it can make it very painful to eat and drink.

Good nutrition is important for people with cancer. If mouth pain or sores make it hard to eat or swallow, your transplant team can help you develop a plan to manage your symptoms.

Because chemotherapy drugs can cause severe nausea and vomiting, doctors often give anti-nausea medicines at the same time as chemo to try to prevent it. As much as possible, the goal is to prevent nausea and vomiting, because its easier to prevent it than it is to stop it once it starts. Preventive treatment should start before chemo is given and should continue for as long as the chemo is likely to cause vomiting, which can be up to 7 to 10 days after the last dose.

No one drug can prevent or control chemo-related nausea and vomiting 100% of the time. In many cases, two or more medicines are used. Youll need to tell your transplant team how well the medicines are controlling your nausea and vomiting. If they arent working, they will need to be changed.

For at least the first 6 weeks after transplant, until the new stem cells start making white blood cells (engraftment), you can easily get serious infections. Bacterial infections are most common during this time, but viral infections that were controlled by your immune system can become active again. Fungal infections can also be an issue. And even infections that cause only mild symptoms in people with normal immune systems can be quite dangerous for you. This is because right after the transplant you don't have many white blood cells that are working well, and they are the primary immune cells that fight off infections.

You may be given antibiotics to try to prevent infections until your blood counts reach a certain level. For instance, pneumocystis pneumonia (often called PCP) is a common infection thats easy to catch. Even though the germ doesnt harm people with normal immune systems, for others it can cause fever, cough, and serious breathing problems. Antibiotics are often used to keep transplant patients from getting this.

Your doctor may check you before the transplant for signs of certain infections that may become active after transplant, and give you special medicines to keep those germs under control. For example, the virus called CMV (cytomegalovirus) is a common infection that many adults have or had in the past. Adults with healthy immune systems may not have any symptoms because their immune system can keep the virus under control. But, CMV can be a cause of serious pneumonia in people who have had transplants, because the transplant lowers the amount of white blood cells they have. Pneumonia from CMVmainly happens to people who were already infected with CMV, or whose donor had the virus. If neither you nor your donor had CMV, the transplant team might follow special precautions to prevent this infection while you are in the hospital.

After engraftment, the risk of infection is lower, but it still can happen. It can take 6 months to a year after transplant for the immune system to work as well as it should. It can take even longer for patients with graft-versus-host disease (GVHD, see below). It's important to talk to your cancer care team about your risk for infection during this time.

Because of the increased risk, you will be watched closely for signs of infection, such as fever, cough, shortness of breath, or diarrhea. Your doctor may check your blood often, and extra precautions will be needed to keep you from being exposed to germs. While in the hospital, everyone who enters your room must wash their hands well. They may also wear gowns, shoe coverings, gloves, and masks.

Since flowers and plants can carry bacteria and fungi, theyre not allowed in your room. For the same reason, you may be told not to eat certain fresh fruits and vegetables. All your food must be well cooked and handled very carefully by you and family members. You might need to avoid certain foods for a while.

You may also be told to avoid contact with soil, feces (stool, both human and animal), aquariums, reptiles, and exotic pets. Your team may tell you to avoid being near disturbed soil, bird droppings, or mold. You will need to wash your hands after touching pets. Your family may need to move the cats litter box away from places you eat or spend your time. Also, you should not clean pet cages or litter boxes during this time. Instead, give this task to a family member or friend.

Your transplant team will tell you and your family in detail about the precautions you need to follow. There are many viruses, bacteria, and fungi that can cause infection after your transplant. You may be at risk for some more than others.

Despite all these precautions, patients often develop fevers, one of the first signs of infection. In fact, sometimes fever is the only sign of infection, so it's very important to contact your cancer care team if you have one or if you have any other signs of infection. You'll probably be asked to take your temperature by mouth every day or twice a day for a while. And your cancer care team will let you know when you should call in your temperature to them. If you get a fever, tests will be done to look for possible causes of the infection (chest x-rays, urine tests, and blood cultures) and antibiotics will be started.

After transplant, youre at risk for bleeding because the conditioning treatment destroys your bodys ability to make platelets. Platelets are the blood cells that help blood to clot. While you wait for your transplanted stem cells to start working, your transplant team may have you follow special precautions to avoid injury and bleeding.

Platelet counts are low for at least several weeks after transplant. In the meantime, you might notice easy bruising and bleeding, such as nosebleeds and bleeding gums. If your platelet count drops below a certain level, a platelet transfusion may be needed. Youll need to follow precautions until your platelet counts stay at safe levels.

It also takes time for your bone marrow to start making red blood cells, and you might need red blood cell transfusions from time to time as you recover.

For more information on the transfusion process, see Blood Transfusion and Donation.

Pneumonitis is a type of inflammation (swelling) in lung tissue thats most common in the first 100 days after transplant. But some lung problems can happen much later even 2 or more years after transplant.

Pneumonia caused by infection happens more often, but pneumonitis may be caused by radiation, graft-versus-host disease, or chemo rather than germs. Its caused by damage to the areas between the cells of the lungs (called interstitial spaces).

Pneumonitis can be severe, especially if total body irradiation was given with chemo as part of the pre-transplant (conditioning) treatment. Chest x-rays will be taken in the hospital to watch for pneumonitis as well as pneumonia. Some doctors will do breathing tests every few months if you have graft-versus-host disease (see next section).

You should report any shortness of breath or changes in your breathing to your doctor or transplant team right away. There are many other types of lung and breathing problems that also need to be handled quickly.

Graft-versus-host disease (GVHD) can happen in allogeneic transplants when the immune cells from the donor see your body as foreign. (Remember: The recipients immune system has mostly been destroyed by conditioning treatment and cannot fight back, so the new stem cells make up most of the immune system after transplant.) The donor immune cells may attack certain organs, most often the skin, gastrointestinal (GI) tract, and liver. This can change the way the organs work and increase the chances of infection.

GVHD reactions are very common and can range from barely noticeable to life-threatening. Doctors think of GVHD as acute or chronic. Acute GVHD starts soon after transplant and lasts a short time. Chronic GVHD starts later and lasts a long time. A person could have one, both, or neither type of GVHD.

Acute GVHD can happen 10 to 90 days after a transplant, though the average time is around 25 days.

About one-third to one-half of allogeneic transplant recipients will develop acute GVHD. Its less common in younger patients and in those with closer HLA matches between donor and the patient.

The first signs are usually a rash, burning, and redness of the skin on the palms and soles. This can spread over the entire body. Other symptoms can include:

Doctors try to prevent acute GVHD by giving drugs that suppress the immune system, such as steroids (glucocorticoids), methotrexate, cyclosporine, tacrolimus, or certain monoclonal antibodies. These drugs are given before acute GVHD starts and can help prevent serious GVHD. Still, mild GVHD will almost always happen in allogeneic transplant patients. Other drugs are being tested in different combinations for GVHD prevention.

The risk of acute GVHD can also be lowered by removing immune cells called T-cells from the donor stem cells before the transplant. But this can also increase the risk of viral infection, leukemia relapse, and graft failure (which is discussed later). Researchers are looking at new ways to remove only certain cells, called alloactivated T-cells, from donor grafts. This would reduce the severity of GVHD and still let the donor T-cells destroy any cancer cells left.

If acute GVHD does occur, it is most often mild, mainly affecting the skin. But sometimes it can be more serious, or even life-threatening.

Mild cases can often be treated with a steroid drug applied to the skin (topically) as an ointment, cream, or lotion, or with other skin treatments. More serious cases of GVHD might need to be treated with a steroid drug taken as a pill or injected into a vein. If steroids arent effective, other drugs that affect the immune system can be used.

Chronic GVHD

Chronic GVHD can start anywhere from about 90 to 600 days after the stem cell transplant. A rash on the palms of the hands or the soles of the feet is often the earliest sign. The rash can spread and is usually itchy and dry. In severe cases, the skin may blister and peel, like a bad sunburn. A fever may also develop. Other symptoms of chronic GVHD can include:

Chronic GVHD is treated with medicines that suppress the immune system, much like those used for acute GVHD. These drugs can increase your risk of infection for as long as you are treated for GVHD. Most patients with chronic GVHD can stop the immunosuppressive drugs after their symptoms improve.

Hepatic veno-occlusive disease (VOD) is a serious problem in which tiny veins and other blood vessels inside the liver become blocked. Its not common, and it only happens in people with allogeneic transplants, and mainly in those who got the drugs busulfan or melphalan as part of conditioning, or treatment that was given before the transplant.

VOD usually happens within about 3 weeks after transplant. Its more common in older people who had liver problems before the transplant, and in those with acute GVHD. It starts with yellowing skin and eyes, dark urine, tenderness below the right ribs (this is where the liver is), and quick weight gain (mostly from fluid that bloats the belly). It is life-threatening, so early diagnosis of VOD is very important. Researchers continue to find ways to try to measure a person's chances of getting VOD so that treatment can start as soon as possible.

Grafts fail when the body does not accept the new stem cells (the graft). The stem cells that were given do not go into the bone marrow and multiply like they should. Graft failure is more common when the patient and donor are not well matched and when patients get stem cells that have had the T-cells removed. It can also happen in patients who get a low number of stem cells, such as a single umbilical cord unit. Still, its not very common.

Graft failure can lead to serious bleeding and/or infection. Graft failure is suspected in patients whose counts do not start going up within 3 to 4 weeks of a bone marrow or peripheral blood transplant, or within 7 weeks of a cord blood transplant.

Although it can be very upsetting to have this happen, these people can get treated with a second dose of stem cells, if they are available. Grafts rarely fail, but if they do it can result in death.

The type of problems that can happen after a transplant depend on many factors, such as the type of transplant done, the pre-transplant chemo or radiation treatment used, the patients overall health, the patients age when the transplant was done, the length and degree of immune system suppression, and whether chronic graft-versus-host-disease (GVHD) is present and how bad it is. The problems can be caused by the conditioning treatment (the pre-transplant chemotherapy and radiation therapy), especially total body irradiation, or by other drugs used during transplant (such as the drugs that may be needed to suppress the immune system after transplant). Possible long-term risks of transplant include:

The medicines used in transplants can harm the bodys organs, such as the heart, lungs, kidneys, liver, bones/joints, and nervous system. You may need careful follow-up with close monitoring and treatment of the long-term organ problems that the transplant can cause. Some of these, like infertility, should be discussed before the transplant, so you can prepare for them.

Its important to find and quickly treat any long-term problems. Tell your doctor right away if you notice any changes or problems. Physical exams by your doctor, blood work, imaging tests, lung/breathing studies, and other tests will help look for and keep tabs on organ problems.

As transplant methods have improved, more people are living longer and doctors are learning more about the long-term results of stem cell transplant. Researchers continue to look for better ways to care for these survivors to give them the best possible quality of life.

The goal of a stem cell transplant in cancer is to prolong life and, in many cases, even cure the cancer. But in some cases, the cancer comes back (sometimes called relapse or recurrence depending on when it might occur after a transplant). Relapse or recurrence can happen a few months to a few years after transplant. It happens much more rarely 5 or more years after transplant.

If cancer comes back, treatment options are often quite limited. A lot depends on your overall health at that point, and whether the type of cancer you have responds well to drug treatment. Treatment for those who are otherwise healthy and strong may include chemotherapy or targeted therapy. Some patients who have had allogeneic transplants may be helped by getting white blood cells from the same donor (this is called donor lymphocyte infusion) to boost the graft-versus-cancer effect. Sometimes a second transplant is possible. But most of these treatments pose serious risks even to healthier patients, so those who are frail, older, or have chronic health problems are often unable to have them.

Other options may include palliative (comfort) care, or a clinical trial of an investigational treatment. Its important to know what the expected outcome of any further treatment might be, so talk with your doctor about the purpose of the treatment. Be sure you understand the benefits and risks before you decide.

Along with the possibility of the original cancer coming back (relapse) after it was treated with a stem cell transplant, there is also a chance of having a second cancer after transplant. Studies have shown that people who have had allogeneic transplants have a higher risk of second cancer than people who got a different type of stem cell transplant.

A cancer called post-transplant lymphoproliferative disease (PTLD), if it occurs, usually develops within the first year after the transplant. Other conditions and cancers that can happen are solid tumor cancers in different organs, leukemia, and myelodysplastic syndromes. These other conditions, if they occur, tend to develop a few years or longer after the transplant.

Risk factors for developing a second cancer are being studied and may include:

Successfully treating a first cancer gives a second cancer time (and the chance) to develop. No matter what type of cancer is treated, and even without the high doses used for transplant, treatments like radiation and chemo can lead to a second cancer in the future.

Post-transplant lymphoproliferative disorder (PTLD) is an out-of-control growth of lymph cells, actually a type of lymphoma, that can develop after an allogeneic stem cell transplant. Its linked to T-cells (a type of white blood cell that is part of the immune system) and the presence of Epstein-Barr virus (EBV). T-cells normally help rid the body of cells that contain viruses. When the T-cells arent working well, EBV-infected B-lymphocytes (a type of white blood cell) can grow and multiply. Most people are infected with EBV at some time during their lives, but the infection is controlled by a healthy immune system. The pre-transplant treatment given weakens the immune system, allowing the EBV infection to get out of control, which can lead to a PTLD.

Still, PTLD after allogeneic stem cell transplant is fairly rare. It most often develops within 1 to 6 months after allogeneic stem cell transplant, when the immune system is still very weak.

PTLD is life-threatening. It may show up as lymph node swelling, fever, and chills. Theres no one standard treatment, but its often treated by cutting back on immunosuppressant drugs to let the patients immune system fight back. Other treatments include white blood cell (lymphocyte) transfusions to boost the immune response, using drugs like rituximab to kill the B cells, and giving anti-viral drugs to treat the EBV.

Even though PTLD doesnt often happen after transplant, its more likely to occur with less well-matched donors and when strong suppression of the immune system is needed. Studies are being done to identify risk factors for PTLD and look for ways to prevent it in transplant patients who are at risk.

Most people who have stem cell transplants become infertile (unable to have children). This is not caused by the cells that are transplanted, but rather by the high doses of chemo and/or radiation therapy used. These treatments affect both normal and abnormal cells, and often damage reproductive organs.

If having children is important to you, or if you think it might be important in the future, talk to your doctor about ways to protect your fertility before treatment. Your doctor may be able to tell you if a particular treatment will be likely to cause infertility.

After chemo or radiation, some women may find their menstrual periods become irregular or stop completely. This doesnt always mean they cannot get pregnant, so birth control should be used before and after a transplant. The drugs used in transplants can harm a growing fetus.

The drugs used during transplant can also damage sperm, so men should use birth control to avoid starting a pregnancy during and for some time after the transplant process. Transplants may cause temporary or permanent infertility for men as well. Fertility returns in some men, but the timing is unpredictable. Men might consider storing their sperm before having a transplant.

For more information on having children after being treated for canceror sexual problems related to cancer treatment, see Fertility and Sexual Side Effects.

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Stem Cell or Bone Marrow Transplant Side Effects

Bone Marrow Stem Cells Comments Off on Stem Cell or Bone Marrow Transplant Side Effects | December 19th, 2020

18 months into the first serious clinical trials of CRISPR gene therapy for sickle cell disease and beta-thalassemiaand all patients are free from symptoms and have not needed blood transfusions.

Sickle cell disease (SCD) can cause a variety of health problems including episodes of severe pain, called vaso-occlusive crises, as well as organ damage and strokes.

Patients with transfusion-dependent thalassemia (TDT) are dependent on blood transfusions from early childhood.

The only available cure for both diseases is a bone marrow transplant from a closely related donor, an option that is not available for the vast majority of patients because of difficulty locating matched donors, the cost, and the risk of complications.

In the studies, the researchers goal is to functionally cure the blood disorders using CRISPR/Cas9 gene-editing by increasing the production of fetal hemoglobin, which produces normal, healthy red blood cells as opposed to the misshapen cells produced by faulty hemoglobin in the bodies of individuals with the disorders.

The clinical trials involve collecting stem cells from the patients. Researchers edit the stem cells using CRISPR-Cas9 and infuse the gene-modified cells into the patients. Patients remain in the hospital for approximately one month following the infusion.

Prior to receiving their modified cells, the seven patients with beta thalassemia required blood transfusions approximately every three to four weeks and the three patients with SCD suffered episodes of severe pain roughly every other month.

All the individuals with beta thalassemia have been transfusion independent since receiving the treatment, a period ranging between two and 18 months.

Similarly, none of the individuals with SCD have experienced vaso-occlusive crises since CTX001 infusion. All patients showed a substantial and sustained increase in the production of fetal hemoglobin.

15 months on, and the first patient to receive the treatment for SCD, Victoria Gray, has even been on a plane for the first time.

Before receiving CRISPR gene therapy, Gray worried that the altitude change would cause an excruciating pain attack while flying. Now she no longer worries about such things.

She told NPR of her trip to Washington, D.C: It was one of those things I was waiting to get a chance to do It was exciting. I had a window. And I got to look out the window and see the clouds and everything.

MORE: MIT Researchers Believe Theyve Developed a New Treatment for Easing the Passage of Kidney Stones

This December, theNew England Journal of Medicinepublishedthe first peer-reviewed research paperfrom the studyit focuses on Gray and the first TDT patient who was treated with an infusion of billions of edited cells into their body.

There is a great need to find new therapies for beta thalassemia and sickle cell disease, saidHaydar Frangoul, MD,Medical Director of Pediatric Hematology and Oncology at Sarah Cannon Research Institute, HCA Healthcares TriStar Centennial Medical Center. What we have been able to do through this study is a tremendous achievement. By gene editing the patients own stem cells we may have the potential to make this therapy an option for many patients facing these blood diseases.

READ: For the First Time in the US, Surgeons Pump New Life into Dead Donor Heart for Life-Saving Transplant

Because of the precise way CRISPR-Cas9 gene editing works, Dr. Frangoul suggested the technique could potentially cure or ameliorate a variety of diseases that have genetic origins.

As GNN has reported, researchers are already using CRISPR to try and treat cancer, Parkinsons, heart disease, and HIV, as well.

Source: American Society of Hematology

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Every Patient Treated With CRISPR Gene Therapy for Blood Diseases Continues to Thrive, More Than a Year On - Good News Network

Bone Marrow Stem Cells Comments Off on Every Patient Treated With CRISPR Gene Therapy for Blood Diseases Continues to Thrive, More Than a Year On – Good News Network | December 19th, 2020

Stem cell transplants from bone marrow or blood offer lifesaving treatment. They are also taxing physically and emotionally.

Its important to know:

What are stem cells?

Blood cells are short-lived and must be replaced. Blood-forming stem cells (hematopoietic cells)divide and multiply. Some mature into one of three blood cell types:

Stem cells are found in bone marrow, in the bloodstream and in umbilical cord blood. In the bloodstream, they are called peripheral blood stem cells (PBSCs). Stem cells from any of these sources can be used in transplants.

What are stem cell transplants?

With a stem cell transplant, a doctor gives you healthy replacementcells that help you fight infection and disease. Doctors most often use stem cell transplants to treat blood disorders and blood cancers that:

A transplant is like a blood transfusion. There are three types:

How stem cell transplants work

Youundergo a process called conditioning. Chemotherapy, radiation therapy or both are used todestroycancer cells and healthy cells that could keep your body from accepting transplanted cells.

New cells are added toyour bloodstream with an IV. The cellscollect in your bone marrow, where they produce new blood cells. Because conditioning leaves your immune system weak, you will need two to three weeks of monitoring.

Who gets a transplant?

At the OHSU Knight Cancer Institute, we consider every person with blood cancer for a stem cell transplant. It might be right for you if your cancer didnt respond to other treatment or if your cancer came back after treatment.

Our providers meet at weekly gatherings called tumor boards to develop the best treatment options for each patient.

Our team considers factors such as your:

Youll want to consider:

What disorders do transplants treat?

Bone marrow/stem cell transplants may be an option to treat:

Leukemias:

Lymphomas:

Other blood cancers and blood disorders:

Other conditions:

Types of stem cell transplants

There are two main types of transplants, each with risks and benefits. OHSU is the only place in Oregon that offers allogeneic transplants.

Autologous transplant

What is it?This type uses your own stem cells. This eliminates the risk of your body rejecting donor cells or of donor cells attacking your body. A relapse may be more likely, though, because you wont have healthy donated cells to attack any diseased cells that remain after conditioning.

How it works:Your care team collects bone marrow using a hollow needle or draws blood and uses a machine to separate out stem cells. The stem cells are frozen. After the conditioning process, the cells are transplanted using anIV drip.

Allogeneic transplant

What is it? We use cells from a donor. Sometimes your own cells are too diseased to collect and reuse. Donor cells are more aggressive in killing any diseased cells left after conditioning. The risk is that they may aggressively target your healthy cells as well, a complication called graft-versus-host disease.

How it works: After the conditioning process, we transplant healthy donor cells using anIV drip. The donor cells help your body rebuild your immune system. A donor can be a relative or someone else whose marrow matches yours.

Allogeneic transplants include:

Bone marrow donors

OHSU has participated in Be The Match: The National Marrow Donor Program since 1996. This program helps people find a lifesaving marrow or PBSC donor. Donors must meet medical guidelinesand should expect to spend 20 to 30 hours in treatment over four to six weeks.

Testing:To find the closest match, doctors will test your blood and a potential donors blood to find their human leukocyte antigen (HLA) type.

HLA markers:Everyone inherits a set of HLA markers from their parents. These markers, contained in almost all of your cells, tell your body which cells belong to you. The more matching markers you and a donor have, the better your chances of a successful transplant. OHSU has success with haploidentical transplants, however, in which as few as half the markers match.

Transplant risks

As with any procedure, transplants involve risks. Your care team will discuss these with you in detail.

Infection: Chemotherapy and radiation therapy weaken your immune system. You are at high risk of infection for up to six weeks until your new cells make healthy blood cells. Your care team will keep you in a safe environment with protection against airborne germs. You will receive safety instructions for going home.

Low platelets:Your platelets will be low for three or more weeks. We will take great care to help you avoid injury or bleeding. Some patients may need a blood transfusion to replace platelets.

Pain:Mouth or throat pain is a common side effect of chemotherapy and radiation therapy. It may cause difficulty eating or swallowing for a few weeks.

Graft failure: Transplant (graft) failure occurs when the body rejects the donor cells. This is rare with stem cell transplants but more common when HLA types are poorly matched.

Graft-versus-host disease:This happens when transplanted cells from the donor attack the recipients tissue and organs. This common complication can range from mild to life-threatening.

Organ damage:Chemotherapy and radiation can leave lasting damage. Well monitor you closely for signs of any problem.

Infertility:The chemotherapy and radiation therapy used before transplants typically result in infertility. OHSU fertility expertscan offer options to preserve your ability to have children before treatment begins.

Physical and emotional effects

Transplants are difficult. They require weeks in or near the hospital, away from work and regular activities. Our cancer social workerscan provide support to you and your family before, during and after treatment:

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Understanding Bone Marrow/Stem Cell Transplant | Knight ...

Bone Marrow Stem Cells Comments Off on Understanding Bone Marrow/Stem Cell Transplant | Knight … | December 17th, 2020

NEW YORK, Dec. 17, 2020 /PRNewswire/ -- Physio Logic, a leading provider of integrated health services in New York City and surrounding areas, continues to demonstrate its commitment to excellence in the field of Regenerative Medicine and Stem Cell Therapy by entering into a collaboration with Regenexx, a worldwide network of specially trained physicians providing the world's most advanced, research-driven, regenerative medicine and stem cell therapy treatments. The partnership brings cutting-edge regenerative treatments to New York City residents suffering from sports injuries or degenerative diseases.

The Regenerative Medicine division of Physio Logic is led by Dr. Tanuj Palvia, MD, a specialist in regenerative medicine and interventional orthopedics focused on the treatment of musculoskeletal injuries and degenerative orthopedic conditions.

"Stem Cell Therapy is one of the most innovative treatments available today but, being so new, patients need to know they're receiving the best possible care. As a physician, I hold myself and my practice to the highest standards and, being aligned with Regenexx adds that extra assurance patients need to know they're in good hands. Whether it's a nagging sports injury or slow degeneration, you're going to get the highest quality of integrated care right here at Physio Logic," said Dr. Palvia.

Interventional Orthobiologics is a specialty that focuses on using your body's natural healing agents to treat orthopedic injuries with the goal of reducing pain and improving joint function. The variety of orthobiologics available to Regenexx physicians, such as bone marrow stem cells and platelet-rich plasma (PRP), allow them to create a treatment plan to best support your recovery. It can be used in the treatment of conditions such as arthritis and injury to ligaments, tendons, cartilage, or bone.

"Being selected to represent the Regenexx brand in New York City speaks to the quality of our facility, our providers, and the care we give our patients," said Dr. Rudy Gehrman, CEO & Founder of the Brooklyn based clinic. "Physio Logic is raising the standard of healthcare in New York and our partnership with Regenexx is an extension of the quality, integrative care we provide to every patient that walks through our door."

Regenexx physicians are required to have thousands of hours of experience performing precise, injection-based treatments using image guidance for a range of body parts and injuries. Their strict acceptance criteria means that Regenexx only chooses the most qualified physicians to join their network. Physio Logic's Interventional Pain Specialist, Dr. Tanuj Palvia, MD, is ranked among them.

To learn more about Physio Logic and Regenerative Medicine, go to https://physiologicnyc.com/regenerative-medicine/

About Physio LogicPhysio Logic brings together an expert team of open-minded medical doctors, physical therapists, chiropractors, acupuncturists, massage therapists, nutritionists, health coaches, biohackers, and Pilates instructors. Our unique collaborative approach, coupled with our ability to assess patients holistically, is used to create a custom care plan tailored to patients' needs. For more information on Physio Logic, visit https://physiologicnyc.com or call (718) 260-1000.

About RegenexxRegenexx is a nationwide network of physicians who practice Interventional Orthopedics, a new specialty that focuses on using the most advanced regenerative protocols available as an alternative to many orthopedic surgeries. Regenexx has published roughly half of the research worldwide on the use of orthobiologics for treating orthopedic injuries, and our patented treatment lab-processing and treatment protocols allow us to achieve unmatched results. Our procedures use your body's natural healing agents including blood platelets and bone marrow concentrate to repair damaged bone, muscle, cartilage, tendons and ligaments. For more information on Regenexx, visit https://regenexx.com.

Media contact:Alan Sott[emailprotected](718) 260-1000

SOURCE Physio Logic

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Physio Logic Brings Cutting-edge Regenerative Treatments for Sport Injuries and Arthritis to New York City - PRNewswire

Bone Marrow Stem Cells Comments Off on Physio Logic Brings Cutting-edge Regenerative Treatments for Sport Injuries and Arthritis to New York City – PRNewswire | December 17th, 2020

The stock price of Creative Medical Technology Holdings Inc (OTCMKTS: CELZ) a company that engages in stem cell research and developing applications to treat male sexual dysfunction and related issues increased by 80.77% yesterday as it went from $0.0026 to $0.0047 per share. One of the biggest triggers for the stock price increase is an announcement about the company announcing the successful application of ImmCelz immunotherapy for treatment of stroke.

In an animal model of ischemia stroke, the middle cerebral artery ligation model, administration of ImmCelz resulted in 34% reduction in infarct volume, whereas control bone marrow mesenchymal stem cells reduced infarct volume by 21%. And there were improvements in functional recovery were observed using the Rotarod test.

At 28 days after induction of stroke the animals receiving ImmCelz had superior running time (92% of non-stroke controls) compared to animals that received bone marrow mesenchymal stem cells (73% of non-stroke control). And animals that received saline had a running time that was 50% of non-stroke controls.

KEY QUOTES:

The regenerative potential of immune cells that have been programmed by stem cells is a fascinating and novel area of research. Conceptual advantages of using reprogrammed T cells include higher migratory ability due to smaller size, as well as ability to replicate and potentially formregenerative memory cells.

Dr.Amit Patel, coinventor of ImmCelz

This data, which is covered by our previous filed patents, such as no. 15/987739,Generation of autologous immune modulatory cells for treatment of neurological conditions, demonstrate that immune modulation via this stem cell based method may be a novel and superior way of addressing the$30 billion dollarmarket for stroke therapeutics. The fact that this technology, which has priority back to 2017, is demonstrating such stunning results, motivates us to consider filing an Investigational New Drug Application for use in stroke.

Dr.Thomas Ichim, coinventor of the patent and Chief Scientific Officer of Creative Medical Technology

While stroke historically has been a major area of unmet medical need, the rise in stroke cases , as well as the fact that younger people are increasingly falling victim to stroke, strongly motivates us to accelerate our developmental programs and to continue to explore participation of Big Pharma in this space. We are eager to replicate the existing experiments start compiling the dossier needed to take ImmCelz into humans using the Investigational New Drug Application (IND) route through the FDA.

Timothy Warbington, President and CEO of Creative Medical Technology

Disclaimer: This content is intended for informational purposes. Before making any investment, you should do your own analysis.

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Creative Medical Technology Stock Price Increased 80.77%: Why It Happened - Pulse 2.0

Bone Marrow Stem Cells Comments Off on Creative Medical Technology Stock Price Increased 80.77%: Why It Happened – Pulse 2.0 | December 17th, 2020

PHILADELPHIA, Dec. 17, 2020 /PRNewswire/ --Immunotherapies, such as checkpoint inhibitor drugs, have made worlds of difference for the treatment of cancer. Most clinicians and scientists understand these drugs act on what's known as the adaptive immune system, the T cells and B cells that respond to specific threats to the body.

New research from a team co-led by Penn Dental Medicine's George Hajishengallis suggests that the innate immune system, which responds more generally to bodily invaders, may be an important yet overlooked component of immunotherapy's success.

Their work, published in the journal Cell, found that "training" the innate immune system with -glucan, a compound derived from fungus, inspired the production of innate immune cells, specifically neutrophils, that were programmed to prevent or attack tumors in an animal model.

"The focus in immunotherapy is placed on adaptive immunity, like checkpoint inhibitors inhibit the interaction between cancer cells and T cells," says Hajishengallis. "The innate immune cells, or myeloid cells, have not been considered so important. Yet our work suggests the myeloid cells can play a critical role in regulating tumor behavior."

The current study builds on earlier work by Hajishengallis and a multi-institutional team of collaborators, which showed that trained immunity, elicited through exposure to the fungus-derived compound -glucan, could improve immune recovery after chemotherapy in a mouse model.

In that previous study, the researchers also showed that the "memory" of the innate immune system was held within the bone marrow, in hematopoietic stem cells that serve as precursors of myeloid cells, such as neutrophils, monocytes, and macrophages.

The team next wanted to get at the details of the mechanism by which this memory was encoded. "The fact that -glucan helps you fight tumors doesn't necessarily mean it was through trained immunity," says Hajishengallis.

To confirm that link, the researchers isolated neutrophils from mice that had received the innate immune training via exposure to -glucan and transferred them, along with cells that grow into melanoma tumors, to mice that had not received -glucan. Tumor growth was significantly dampened in animals that received cells from mice that had been trained.

-glucan is already in clinical trials for cancer immunotherapy, but the researchers say this finding suggests a novel mechanism of action with new treatment approaches.

"This is a breakthrough concept that can be therapeutically exploited for cancer immunotherapy in humans," Hajishengallis says, "specifically by transferring neutrophils from -glucan-trained donors to cancer patients who would be recipients."

Contact: Beth Adams, [emailprotected]

SOURCE Penn Dental Medicine

http://www.dental.upenn.edu

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Priming the Immune System to Fight Cancer - PRNewswire

Bone Marrow Stem Cells Comments Off on Priming the Immune System to Fight Cancer – PRNewswire | December 17th, 2020

Today, we take an in-depth look at an intriguing development concern with one product approved and on the market and more importantly a more lucrative candidate that appears on its way to approval in Europe. A full analysis on this Busted IPO follows in the paragraphs below.

Orchard Therapeutics (ORTX) is a London, United Kingdom-based biopharmaceutical company that IPO'd in 2018. The company is focused on developing gene therapies for rare conditions. In 2018, Orchard acquired GSK's rare disease gene therapy portfolio, which originated from a collaboration between GSK and the San Raffaele Telethon Institute for Gene Therapy. The company's unique approach involves inserting a working copy of the missing or malfunctioning gene into a patient's own blood stem cells. This approach circumvents the need for a bone marrow transplant since it leverages blood stem cells intrinsic capacity to self-renew in a patient's bone marrow and produce new blood cells of all types. The company's overarching goal is to permanently correct genetic disorders via a single treatment.

The company does have one approved product called Strimvelis, which is indicated for patients with severe combined immunodeficiency due to adenosine deaminase deficiency for whom no suitable human leukocyte antigen matched related stem cell donor is available; however, the drug has only been approved by the EMA and not the FDA. The company's pipeline is candidate rich, spanning a variety of indications that are compartmentalized into three categories: neurometabolic/neurodegenerative disorders, immunological disorders, and blood disorders. The company has a couple of late-stage candidates. Orchard Therapeutics has a market capitalization of roughly $450 million and trades for approximately $4.50 a share.

Pipeline

Source: Company Presentation

OTL-200

OTL-200 is an ex vivo autologous gene therapy in development to treat metachromatic leukodystrophy. The drug uses a modified virus to insert an operational copy of the ARSA gene into a patient's cells. OTL-200 has received rare pediatric disease designation from the FDA. MLD is a rare and deadly inherited disease. The disease is characterized by the accumulation of fats called sulfatides, which causes a breakdown in the protective fatty layer surrounding nerves in the central and peripheral nerve systems. It is estimated that 1 in 40,000 to 1 in 160,000 people have the disease worldwide. OTL-200 was developed in partnership with the San Raffaele Telethon Institute for Gene Therapy.

Source: Company Presentation

On October 16th, the company announced that it received a positive CHMP opinion for the drug, which recommended full marketing authorization for the treatment of early-onset metachromatic leukodystrophy patients in the European Union. The positive opinion will now be reviewed by the European Commission. A final decision is expected by the end of 2020. If approved, the company would be targeting a launch in the first half of 2021.

Furthermore, the company is pursuing a regenerative medicine advanced therapy designation, and it filed an investigational new drug application or IND in the U.S., which was accepted by the FDA on November 19th. Orchard has also applied for Regenerative Medicine Advanced Therapy designation for OTL-200 to help facilitate additional dialogue with the FDA

In addition, within the neurometabolic/neurodegenerative disorders category, it was announced in September that the European Medicines Agency has granted Priority Medicines designation to OTL-203 for the treatment of mucopolysaccharidosis type I. This comes not long after 203 received Orphan Drug designation in the U.S.

Source: Company Presentation

OTL-103

OTL-103 is an ex vivo autologous gene therapy in development to treat Wiskott-Aldrich syndrome. The drug uses a modified virus to insert a working copy of the WAS gene into a patient's cells. WAS is a rare, X-linked, recessive, inherited immune disorder, which is characterized by reoccurring severe infections, autoimmunity, eczema and severe bleeding episodes. The company has received Rare Pediatric Disease designation and Regenerative Medicine Advanced Therapy designation from the FDA. OTL-103 is being developed in partnership with the San Raffaele Telethon Institute for Gene Therapy.

Looking ahead, the company is preparing to file a BLA in the U.S. and an MAA in the EU for OTL-103 in WAS in 2021.

Source: Company Presentation

As of September 30th, 2020, Orchard Therapeutics had cash and cash equivalents of $41.1 million compared to $19 million on December 31st, 2019. Research and development expenses for the third quarter were $14.6 million compared to $28.4 million in Q3 of 2019. Selling, general and administrative expenses were $12.9 million in the quarter compared to $14.2 million in the same quarter of 2019. The company did $1.9 million in product revenue for the quarter compared to $1.9 million in Q3 of 2019. Overall, the company reported a net loss of $20.2 million compared to a net loss of $36.7 million in Q3 of 2019. Management stated in the latest quarterly update that it expects its current financial position to cover its anticipated operating and capital expenditure requirements into 2022.

The company is sparsely covered in the United States despite a healthy market cap as our most names in this space domiciled overseas. The most recent recommendation comes from Oppenheimer on September 14th. The firm lowered its price target from $26 a share to $16 a share, but it maintained its overweight rating. The analyst stated that the updated price target reflects a more subdued opinion on the pace of pipeline development for MPS-1 and MPS-IIIA. It reiterated this rating on November 19th.

Both Barclays ($13 price target, down from $15 previously) and Goldman Sachs ($9 price target, down from $13) reiterated Buy ratings on ORTX albeit revising the price targets lower. Finally, on May 22nd, JPMorgan lowered its price target from $26 a share to $17 a share and maintained its overweight rating. The analyst's note did seem upbeat despite the lowered price target in that the analyst thinks that the company's pipeline possesses "broad potential".

Two things prevent Orchard from being considered for a large holding. First, the company looks like it will have to raise additional capital in the very near future. I think the company will raise capital immediately after the next positive news event. Second, overseas biotech concerns don't ever seem to get the attention from analysts or valuation from investors that companies domiciled in the States do. That said, the company has multiple shots on goal and definable potential catalysts on the near-term potential. Add in the possible wildcard of being a potential buyout target at some point, and ORTX would seem worthy of a small "watch item" stake at this time.

Bret Jensen is the Founder of and authors articles for the Biotech Forum, Busted IPO Forum, and Insiders Forum.

Author's note: I present and update my best small-cap Busted IPO stock ideas only to subscribers of my exclusive marketplace, The Busted IPO Forum. Our model portfolio has crushed the return of the Russell 2000 since its launch in the summer of 2017. To join the Busted IPO Forum community, just click on the logo below.

Disclosure: I am/we are long ORTX. 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.

Originally posted here:
Our View On Orchard Therapeutics - Seeking Alpha

Bone Marrow Stem Cells Comments Off on Our View On Orchard Therapeutics – Seeking Alpha | December 17th, 2020

Osteonecrosis of the femoral head (ONFH) is a refractory disease characterized by compromised subchondral microcirculation, bone necrosis, and microfracture accumulation without sustained compensatory remodeling.1 Its complex etiology, variability in location (lateral, medial, or central), intra-bone edema, and inflammation add to the unpredictable prognosis. Although few patients regress spontaneously, the progressive nature and lack of curative treatment for ONFH thus far are the challenges faced in the management of ONFH.

Osteonecrosis of the femoral head typically affects relatively young, active individuals between 20 and 40 years old and follows an unrelenting course resulting in substantial loss of function.2 The Indian Society of Hip and Knee Surgeons' Registry stated that 49% of total hip arthroplasty procedures in India are due to an irreversible stage of ONFH.3 Osteonecrosis of the femoral head is idiopathic in most cases. Steroid and alcohol consumption are the second most common causes.4 The term silent hip refers to an asymptomatic hip in patients with ONFH of the contralateral hip and is at risk of developing ONFH.5

Hip and groin pain and limp when patients walk are primary indicators. Radiography, magnetic resonance imaging (MRI), and computed tomography are tools for diagnosis, prognosis, and decision-making regarding treatment of ONHF. Crescent formation, collapse and anterolateral sequestration on radiographs, and a double line presentation on T2-weighted MRI provide confirmation of ONFH diagnosis.

The Ficat and Arlet staging of ONFH from I to IV indicates the progressive involvement and progression of the femoral head toward arthritis.6 However, it does not allow prediction of the possibility of progression. Ficat and Arlet stage I with extensive involvement of the femoral head will have a high chance of further progression to collapse. Steinberg grades of ONFH allow prediction of the possibility of progression to collapse in a precollapse hip.7 The Association Research Circulation Osseous (ARCO) takes into consideration the location of the crescent, amount of cartilage depression, and the area and volume of the femoral head affected as reliable predictors of prognosis in early stage ONFH and is helpful for identifying a femoral head at risk of progression and collapse.8

The most common surgical intervention in early stage ONFH is core decompression.9 However, core decompression is notable for its lack of effectivity in preventing collapse in cases where progression is most likely to happen (ie, in cases where there is extensive involvement [more than 30%] of the anterolateral region of the femoral head and crescent sign).10 Among other surgical interventions, fibular graft (vascularized or nonvascularized) proximal femoral osteotomy has been described.11

Hernigou and Beaujean12 reported abnormalities in the mesenchymal stem cell pool, which is known for its regenerative potential, following insult to the affected hip. Gangji et al13 later reported qualitative and quantitative abnormalities of osteoblast cells within the proximal femur in ONFH patients. Thus, it is accepted that the regenerative and reparative capacity of bone in ONFH is severely compromised. However, more than two decades of experience using various orthobiologics has not been convincingly satisfying, and many groups have expressed limitations of these therapies.1416

The pathology of ONFH involves ischemic imbalance of bone remodeling due to relatively enhanced osteoclastic action and poor regenerative potential of osteogenic cells in the proximal femur. The supply of differentiated osteogenic cells (osteoblasts) over time would result in arrest of ONFH progression. Core decompression would allow revascularization, and debridement of necrotic bone decreases the time needed for creeping substitution of new bone over dead bone. With this theoretical conviction, the author planned to use and assess the efficacy of autologous bone marrowderived cultured osteoblasts following core decompression and debridement in the treatment of patients diagnosed with ARCO stages II and III ONFH.

The surgeries were conducted at various hospitals. Fifteen patients (13 male and 2 female), with a mean age of 32 years (range, 2161 years), presented with typical ONFH symptoms. Patients were diagnosed with ARCO stage II or III ONFH (9 bilateral and 6 unilateral, for a total of 24 hips) on radiograph and MRI, and were considered for a predesigned treatment protocol that involved implantation of autologous cultured osteoblasts following core decompression and debridement.

Patient consent for inclusion in the study was obtained. The types of ONFH were idiopathic (8 patients), corticosteroid-induced (6 patients), and traumatic (1 patient) (Table 1). Efficacy of the treatment was assessed based on changes on radiograph and MRI and modified Harris Hip Score (mHHS), Oxford Hip Score (OHS), and visual analog scale (VAS) score after treatment. In a few patients, computed tomography also was performed.

Table 1:

Patient Characteristics

Treatment was performed in 2 steps.

Step 1. Percutaneous bone marrow aspiration from the iliac crest was performed and collected in transport media containing anticoagulant. This was transported under temperature-monitored conditions and processed at a good manufacturing practicecertified cell processing facility to obtain a predefined osteoblast culture (4 to 5 weeks).

The ex vivo culture of osteoblasts using bone marrow from the patient involved isolation of osteoprogenitor cells, osteogenic differentiation, and then expansion. Immunophenotypic characterization was performed to ensure the cultured cells tested positive for CD44+ and CD151+ markers. Alizarin red stain test ensured the presence of calcium deposits within the osteoblasts. Alkaline phosphatase test was used as an indicator of ability to form type I collagen.

Thus, ex vivo cultured live osteoblast cells, not less than 45 million, were filled and packed in sterile vials with appropriate transport/culture medium and were made available for individualized treatment. The cell viability was ensured during transport as well as after implant until the cells were integrated.

Step 2. The surgical implantation was planned as per the availability of cultured and expanded osteoblasts (4 to 5 weeks). In the first 3 patients, the osteoblast implant was performed soon after core decompression, whereas for the remaining 12 patients, core decompression was followed by debridement with implantation.

The location of the necrotic zone and its size was approximated on MRI. The patient was placed on a fracture table, and the C-arm was positioned as for routine core decompression. The entry point of the guidewire (2.5 mm) was chosen around the vastus ridge to allow faster healing in the cancellous bone (Figure 1).

Figure 1:

Surgical process details. The arrow indicates the high entry point of the guidewire at the vastus ridge targeting the area of osteonecrosis. A, 1-cm distance from the superior cortex to prevent fracture. B, varus appearance of the proximal femur due to mild flattening of the femoral head in the anterolateral femur in early osteonecrosis of the femoral head. This is the earliest sign observed radiographically and is indicative of stage IIB.

The larger sagittal dimensions of the trochanteric area allowed for a posterior entry point to avoid a possible subtrochanteric fracture due to posterior cortical breaching during or after intervention. Special effort was made to avoid a subtrochanteric entry point. On no occasion was the posterior cortex of the femur violated. The guidewire was passed in the center of the lesion but at least 1 cm from the superior cortex. An 8-mm cannulated core drill (from the dynamic hip screw set) was used over the wire to make a tunnel until the necrotic zone. The steps of the surgical intervention are shown in Figure 2.

Figure 2:

Surgical steps. Anteroposterior C-arm image of the hip with guidewire (A). Lateral C-arm image of the hip with guidewire (B). Drilling with 8-mm dynamic hip screw core drill bit (C). Anteroposterior C-arm image during curettage (D).

The tip of the drill, when removed, showed necrotic bone (Figure 3A), which was later sent for histopathology. Bone curettes of various sizes and angles then were used to curette the sequestrum under imaging guidance. The end point of curettage was the removal of hard sclerotic bone from the femoral head. If there was a bony ridge that was difficult to curette, a reamer was used. The author attempted to leave 1 cm of subchondral bone intact to allow faster revascularization of the femoral head by removing dead sclerotic bone. Curettes were kept at least 1 cm from the joint line.

Figure 3:

Drill bit with debrided live and dead bone (A). Instruments used during surgery (B).

After curettage was complete, the tunnel was plugged using an allograft of appropriate size. All of the instruments used during surgery are shown in Figure 3B. At this point, the patient was tilted to attain a gravity-dependent position of the operative hip to avoid any backflow of the implanted cells. A spinal needle was inserted through the small hole made in the allograft plug, and the osteoblast cell gel mixture was slowly injected in the space within the femoral head. Patients were held in the same position for approximately 10 minutes to allow the cells to settle without spilling.

Postoperatively, patients were partial weight bearing for 4 weeks using a walker. They progressed to using a walking stick by week 6, and then full weight bearing was permitted by week 8. For patients treated for bilateral ONFH, use of a walker was encouraged until week 6. Physical exercises to regain muscle strength and all hip joint movements were encouraged as soon as possible.

All patients underwent regular follow-up during the rehabilitation period and thereafter at 6, 12, and 18 months, with all anteroposterior and lateral radiographs of the hip and magnetic resonance imaging completed at 18 months. Two patients were lost to follow-up thereafter, and 13 patients continued with regular follow-up visits; 3 patients had follow-up of 7 years.

At 18 months after implant, no disease progression was observed on radiographs and MRIs for all patients. Postoperative mHHS, OHS, and VAS scores improved, and all of the patients had resumed normal routine activities and daily chores. Analysis of variance for HHS, OHS, and VAS scores showed a statistically significant difference (individual as well as mean values) from baseline to 18 months after implantation (P<.5; Table 2). Three patients who underwent follow-up for 7 years after implantation were assessed via telephone for HHS and VAS scores. For 1 of these patients, HHS improved from 90 to 95, and VAS score improved from 3 to 1 at 18 months. For another patient, HHS improved from 85 to 95, and VAS score improved from 2 to 1 at 18 months. One of the patients who underwent follow-up for 7 years walked daily for 3 to 4 km.

Table 2:

Pain and Function-Related Scores

One male patient who was treated for bilateral ONFH with follow-up of 5 years showed good improvement in HHS (from 65 to 92.5) at the end of 18 months, and his VAS score improved from 9 at baseline to 3 in both hips at 18 months after treatment. At 5 years postoperatively, he reported pain only after sitting for several hours and was more comfortable using a cane when walking.

Another male patient was diagnosed with ARCO stage III of the right hip. He had extensive involvement of the central and lateral lesion (>50%) with crescent depression less than 2 mm. Although reports for direct comparison were not available at 6 years after treatment, radiographs showed no further progression, with intramedullary changes evident. The joint space was preserved, which is consistent with good clinical function (Figure 4).

Figure 4:

Patient M4. Preoperative magnetic resonance image of Association Research Circulation Osseous stage III of the right hip. Extensive involvement of the central and lateral regions (>50%), with the crescent having less than 2 mm of depression (A, B). Magnetic resonance image at 5 months after treatment (C). Preoperative anteroposterior radiograph (D). Anteroposterior radiograph at 6 years after treatment showing no further progression, with evident intramedullary changes. The joint space is preserved, which is consistent with good clinical function (E).

One female patient had a history of tuberculosis treated with anti-Koch therapyanti-tubercular therapy and corticosteroids for 9 months as the standard care. This patient presented with extensive bilateral femoral head involvement evident on radiograph and computed tomography scan. The crescent depression was 2 to 4 mm. She was diagnosed with ARCO stage II of the right hip and grade III of the left hip. Radiographs at 6 years postoperatively showed arrest of osteonecrosis progression with an otherwise high risk of collapse because the ONFH was steroid induced. Clinically, this patient was able to resume all of her routine activities, including a daily commute to work and regular yoga, floor exercises, and stationary cycling (Figure 5).

Figure 5:

Patient F1. Preoperative anteroposterior radiographs (A, B). Preoperative computed tomography scans. There is extensive bilateral femoral head involvement (>30%), with 2 to 4 mm of depression of the crescent (C, D). Anteroposterior radiographs 6 months after treatment (E, F). Anteroposterior radiograph 6 years after treatment. Both femoral heads show arrest of osteonecrosis progression in a patient at high risk for collapse (G).

One male patient who was receiving long-term steroid treatment had relatively moderate improvement in HHS, from a baseline of 65 to 80 at 18 months after treatment. A female patient with bilateral ONFH had ARCO stage III in the right hip and a small, centrally located lesion (<30%) in the left hip. On radiograph and MRI, the right hip showed more than 90% involvement of the lateral, central, and medial regions but no crescent. The decision was made not to treat the left hip because it was deemed to have minimum possibility of progression. At 6 years after treatment, there was regression of necrosis. The patient has done well clinically and had a successful childbirth (Figure 6).

Figure 6:

Patient F2. Preoperative anteroposterior radiographs of the right hip showing more than 90% involvement of the medial, central, and lateral regions. There is no crescent (A, B). Preoperative magnetic resonance images (C, D). Anteroposterior radiograph at 3 months after treatment (E). Anteroposterior radiograph at 6 years after treatment (F).

Overall, the short-term and long-term results of autologous cultured osteoblast treatment along with routine procedures have been satisfactory. None of the 8 patients who underwent follow-up for 5 to 7 years showed any signs of disease progression, and none of the patients required repeat treatment or total arthroplasty.

Among invasive procedures, core decompression has been the standard of care for early stages of ONFH; however, varying degrees of improvement have been reported. Yoon et al17 and Rajagopal et al18 reported treatment of ONFH with core decompression was viable only in early stages, with the effect lasting for 2 to 3 years.

Among the biologics, platelet-rich plasma, growth factors, and bone marrow aspirate concentrate (BMAC) have been widely used along with conventional techniques such as core decompression or bone grafts.19,20 Several contributions in terms of understanding the clinical application and efficacy of biologics for the treatment of ONFH have been published during the past two decades.2123 Inherent limitations such as the absence of controlled studies, uncertainty, and heterogenicity of the composition of biologics have resulted in inconsistent results, and no treatment option has passed the regulatory approval process.24

In a recent study, Hauzeur et al25 reported obvious inefficacy of BMAC treatment in a randomized clinical trial comparing BMAC and core decompression vs core decompression alone. Their assessment criteria included clinical outcome, pain score, radiology, and the need for total hip arthroplasty.

Untreated bone marrow should be considered first-generation and processed bone marrow second-generation biological treatments for ONFH. The results using first- and second-generation biologics have been variable, and there are no long-term data and no formally approved products. Thus, curative treatment of ONFH, at least prior to the collapse stage, remains challenging.26

Kim et al27 were the first to report the clinical use of cultured osteoblasts in a single patient with bilateral ONFH (Ficat Arlet grade II); they reported a good outcome at 5 years without progression of disease. Later, Gangji et al28 compared the use of BMAC and autologous osteoblast cells in the treatment of avascular necrosis. They reported the group treated with osteoblast cells had twofold higher respondents at 36 months compared with the BMAC-treated group. These patients continued to have reduced pain until the end of the study period. Also, progression of disease from stage III to IV was more than 2 times higher in the BMAC-treated group compared with the osteoblast-treated group.28

The author proposes the evolution of biologics being used as first- and second-generation treatment, and the current modality of using autologous cultured osteoblasts as the latest and third-generation treatment. As such, the latter is the only modality that qualifies as cell-based therapy (Table 3).

Table 3:

Proposed Generations of Orthobiologics

Autologous cultured osteoblast implant is the most novel treatment modality for joint preservation. In the author's experience, 11 patients at 4 years, 6 patients at 5 years, and 3 patients at 7 years after transplant showed arrest of disease. Joint structure, biomechanics, strength, and function were regained in these patients, and they required no repeat treatment. Yet, unlike few other treatments, total arthroplasty still remains viable as a future option.

The assessment of ONFH progression on MRI after core decompression remains a sparsely studied subject. Therefore, radiographic and clinical examination during follow-up is crucial.

Autologous cultured osteoblast implantation is effective and safe for patients with ARCO stages II and III ONFH. This third-generation biologic can be considered a joint-preserving treatment in correctly chosen patients.

Patient Characteristics

Pain and Function-Related Scores

Proposed Generations of Orthobiologics

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Hip Preservation With Autologous Osteoblast Cell-Based Treatment in Osteonecrosis of the Femoral Head - Healio

Bone Marrow Stem Cells Comments Off on Hip Preservation With Autologous Osteoblast Cell-Based Treatment in Osteonecrosis of the Femoral Head – Healio | December 17th, 2020

Regeneron: Preventing Infection Among Households

Regeneron: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Assessing the Efficacy and Safety of Anti-Spike SARS-CoV-2 Monoclonal Antibodies in Preventing SARS-Cov-2 Infection in Household Contacts of Individuals Infected with SARS-CoV-2

In this multisite trial, researchers are working to determine if monoclonal antibodies made by the drug company Regeneron Pharmaceuticals can prevent COVID-19 infection among people who have been exposed by someone in their household, but have not yet developed the disease. The trial is testing the same antibody cocktail given to President Donald Trump when he was hospitalized with COVID-19, though with a different use.

In this case, the antibodies are intended to prevent people from getting sick if they have a household member with COVID, Enfield said. So far, UVA has done a good job with recruitment, which is particularly tricky in this case as you have to find people who have been exposed to COVID in their household, but who do not yet have COVID.

UVA is recruiting 40 participants for the study, each of whom will receive four injections of either the antibodies or a placebo. Participants must have been exposed to COVID-19 by someone in their household within the previous 96 hours and continue to live with that person for a month.

Its been a rapid process, and a testament to the multidisciplinary team involved, from infectious disease clinicians and researchers to cell therapy, pulmonary critical care and several other departments, Sturek said. Its been all-hands-on-deck.

As results from these and other clinical trials continue to come in, Sturek also expressed hope that we will see widespread and effective vaccine distribution sooner, rather than later.

There is a lot on the horizon, from news around vaccines to getting the first wave of vaccines to high-risk people like health care workers, he said. Every day we learn something new, and its important to stay humble, to be able to adapt and change on the fly.

Fighting this pandemic has been a huge, multidisciplinary effort, and so many people joined in to help contribute and bring new treatments to our patients, and bring new research to the field. That doesnt get done without a huge team of nurses, clinical research coordinators, pharmacists, respiratory therapists and many, many others. It is impossible to overstate the importance of all of that teamwork.

See the article here:
Research That Saves Lives: Four COVID-19 Therapies Being Tested at UVA - University of Virginia

Bone Marrow Stem Cells Comments Off on Research That Saves Lives: Four COVID-19 Therapies Being Tested at UVA – University of Virginia | December 17th, 2020

Autologous hematopoietic stem cell transplant (AHSCT) induces a reduction in relapse rate and physical disability in patients with relapsing-remitting multiple sclerosis (RRMS) who respond inadequately to other treatments, a small study suggests.

The study, Selective cognitive dysfunction and physical disability improvement after autologous hematopoietic stem cell transplantation in highly active multiple sclerosis, was published in the journal Nature Scientific Reports.

AHSCT is an experimental approach to treat multiple sclerosis (MS) that is meant to rebuild a patients immune system in order to stop attacks on the brain and spinal cord.

The procedure begins with collecting a patients own (meaning autologous) healthy hematopoietic stem cells immature cells that can develop into all types of blood cells from the bone marrow. These cells are put back into the patient after a fairly non-aggressive combination of chemotherapy is given to kill the patients immune cells.

A team of researchers at the Vilnius University, in Lithuania, evaluated the effectiveness and safety of the AHSCT procedure in 24 patients (18 female, mean age 37.8 years) with highly active RRMS (mean disease duration of 8.6 years) who failed to respond to conventional therapies.

The aim of the study was to assess cognitive dysfunction and physical disability after AHSCT, to explore the potential factors influencing disability regression after the transplant, and to estimate the safety of low-dose immunosuppressive therapy in highly active relapsing MS patients.

Researchers assessed participants disability and cognition through changes in several functional measures, including the expanded disability status scale (EDSS) and the Brief International Cognitive Assessment for MS, which includes three cognitive domains measured by the symbol digit modalities test, brief visuospatial memory test revised, and California verbal learning test second edition.

Of the 24 patients, 13 (54.2%) completed a 24-month follow-up and were included in the efficacy analysis of AHSCT. From those, two (15.4%) had one relapse during the first year after AHSCT and three patients (23.1%) had one relapse during the second year after AHSCT.

The annualized relapse rate (ARR) was 2.7 one year before AHSCT and 1.9 at two years before AHSCT. After the AHSCT procedure, ARR dropped to 0.2 in the first year and to 0.3 in the second year. This represented an 89% reduction in ARR, when comparing the values at two years after AHSCT with those at two years before AHSCT.

The researchers also noted a reduction in disability progression (as measured by EDSS scores), with 84.6% of patients improving their disability score after AHSCT at month six and 76.9% at one year. Additionally, 76.9% of patients showed stable disability scores two years after the transplant.

The findings of EDSS improvement in almost 85% of the patients suggest that disability may be often at least temporarily reversible in patients with highly active [relapsing] MS if they receive suitable and well-timed treatment, the researchers wrote.

Using appropriate statistical models, researchers found that the clinical variable that explained the disability regression at months 6 and 12 after AHSCT was the disability progression over 6 months before AHSCT.

Improvements in cognition after AHSCT also were observed. Specifically, the scores of information processing speed and verbal learning, measured by the symbol digit modalities test, were significantly higher at month 12 after AHSCT (56.8) when compared to month three (48.3).

The score of brief visuospatial memory test revised that assesses visuospatial memory was slightly lower at month three (25.6) than before AHSCT (27.8), however, the difference was not significant.

The score of the California verbal learning test, which assesses verbal learning, was significantly higher at month 12 (63.6) than before AHSCT (55.2).

No new or active lesions were found on MRI after AHSCT, suggesting that all patients remained without radiological disease activity.

Furthermore, regarding safety, the incidence and severity of adverse events (side effects) after AHSCT were in the expected range and all were resolved. There were no transplant-related deaths reported.

Researchers noted several limitations to the studys findings, including the low sample size and the fact that the patientss assessment and follow-ups were provided at the same center without a comparative group.

Nonetheless, the outcomes are highly promising, as compared to conventional MS treatment, the researchers wrote. Further research is needed to replicate these findings and to assess long-term outcomes and safety of AHSCT.

Diana holds a PhD in Biomedical Sciences, with specialization in genetics, from Universidade Nova de Lisboa, Portugal. Her work has been focused on enzyme function, human genetics and drug metabolism.

Total Posts: 1,053

Patrcia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.

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Stem Cell Transplant Reduces Relapses and Disability in RRMS... - Multiple Sclerosis News Today

Bone Marrow Stem Cells Comments Off on Stem Cell Transplant Reduces Relapses and Disability in RRMS… – Multiple Sclerosis News Today | December 16th, 2020

PHOENIX, Dec. 16, 2020 /PRNewswire/ --Creative Medical Technology Holdings Inc., (OTC CELZ) announced today positive preclinical data supporting the utilization of its ImmCelz cell based immunotherapy for treatment of stroke. In an animal model of ischemia stroke, the middle cerebral artery ligation model, administration of ImmCelz resulted in 34% reduction in infarct volume, whereas control bone marrow mesenchymal stem cells reduced infarct volume by 21%. Additionally, improvements in functional recovery where observed using the Rotarod test. At 28 days after induction of stroke the animals receiving ImmCelz had superior running time (92% of non-stroke controls) compared to animals which received bone marrow mesenchymal stem cells (73% of non-stroke control). Animals that received saline had a running time that was 50% of non-stroke controls.

"The regenerative potential of immune cells that have been programmed by stem cells is a fascinating and novel area of research." Said Dr. Amit Patel, coinventor of ImmCelz, and board member of the Company. "Conceptual advantages of using reprogrammed T cells include higher migratory ability due to smaller size, as well as ability to replicate and potentially form "regenerative memory cells."

"This data, which is covered by our previous filed patents, such as no. 15/987739, Generation of autologous immune modulatory cells for treatment of neurological conditions, demonstrate that immune modulation via this stem cell based method may be a novel and superior way of addressing the $30 billion dollar market for stroke therapeutics1." Said Dr. Thomas Ichim, coinventor of the patent and Chief Scientific Officer of the Company. "The fact that this technology, which has priority back to 2017, is demonstrating such stunning results, motivates us to consider filing an Investigational New Drug Application for use in stroke."

Creative Medical Technology Holdings possesses numerous issued patents in the area of cellular therapy including patent no. 10,842,815 covering use of T regulatory cells for spinal disc regeneration, patent no. 9,598,673 covering stem cell therapy for disc regeneration, patent no. 10,792,310 covering regeneration of ovaries using endothelial progenitor cells and mesenchymal stem cells, patent no. 8,372,797 covering use of stem cells for erectile dysfunction, and patent no. 7,569,385 licensed from the University of California covering a novel stem cell type.

"While stroke historically has been a major area of unmet medical need, the rise in stroke cases , as well as the fact that younger people are increasingly falling victim to stroke, strongly motivates us to accelerate our developmental programs and to continue to explore participation of Big Pharma in this space." Said Timothy Warbington, President and CEO of the Company. "We are eager to replicate the existing experiments start compiling the dossier needed to take ImmCelz into humans using the Investigational New Drug Application (IND) route through the FDA."

About Creative Medical Technology Holdings

Creative Medical Technology Holdings, Inc. is a commercial stage biotechnology company specializing in stem cell technology in the fields of urology, neurology and orthopedics and trades on the OTC under the ticker symbol CELZ. For further information about the company, please visitwww.creativemedicaltechnology.com.

Forward Looking Statements

OTC Markets has not reviewed and does not accept responsibility for the adequacy or accuracy of this release. This news release may contain forward-looking statements including but not limited to comments regarding the timing and content of upcoming clinical trials and laboratory results, marketing efforts, funding, etc. Forward-looking statements address future events and conditions and, therefore, involve inherent risks and uncertainties. Actual results may differ materially from those currently anticipated in such statements. See the periodic and other reports filed by Creative Medical Technology Holdings, Inc. with the Securities and Exchange Commission and available on the Commission's website atwww.sec.gov.

Timothy Warbington, CEO[emailprotected] CreativeMedicalHealth.com

Creativemedicaltechnology.comwww.StemSpine.comwww.Caverstem.comwww.Femcelz.com

1 Stroke Management Market Size Forecasts 2026 | Statistics Report (gminsights.com)

SOURCE Creative Medical Technology Holdings, Inc.

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Creative Medical Technology Holdings Announces Successful Application of ImmCelz Immunotherapy for Treatment of Stroke - PRNewswire

Bone Marrow Stem Cells Comments Off on Creative Medical Technology Holdings Announces Successful Application of ImmCelz Immunotherapy for Treatment of Stroke – PRNewswire | December 16th, 2020

Cancer researchers have created a new class of drugs to selectively target and destroy myeloid leukaemia cells with TET gene mutations.

Photomicrograph of bone marrow biopsy showing myeloblasts of acute myeloid leukemia (AML), a cancer of white blood cells.

Researchers have developed a novel class of targeted cancer drug that may be highly effective for the treatment of myeloid leukaemias. According to the team, their synthetic molecule, called TETi76, was able to selectively kill cells with TET2 gene mutations, one of the most common driver mutations in myeloid leukaemias.

Myeloid leukaemias are cancers derived from stem and progenitor cells in the bone marrow that give rise to all normal blood cells. These malignancies are normally treated with chemotherapy, either alone or in combination with targeted drugs; however, the significant side-effects associated with this treatment mean a more selective/targeted treatment is desirable.

In a new study published inBlood Cancer Discovery, researchers from the Cleveland Clinics Taussig Cancer Institute and Lerner Research Institute, both US, describe a new pharmacological strategy to preferentially target and eliminate leukaemia cells with TET2 mutations.

In preclinical models, we found that a synthetic molecule called TETi76 was able to target and kill the mutant cancer cells both in the early phases of disease what we call clonal haematopoiesis of indeterminate potential, or CHIP and in fully developed TET2 mutant myeloid leukaemia, said Dr Jaroslaw Maciejewski, a practicing haematologist and chair of the Cleveland Clinic Department of Translational Hematology & Oncology Research, who has been investigating the TET2 gene for the last decade.

TET genes encode DNA dioxygenase enzymes, which remove chemical groups from DNA molecules. Their activity ultimately changes what genes are expressed and can contribute to the development and spread of disease.

TET genes act as tumour suppressors, so loss-of-function mutations are common in haematological cancers, like leukaemias. While all members of the TET family are dioxygenases, TET2 is the most powerful. Genetic TET2 deficiency has been shown to skew differentiation of blood cells and clonal expansion of progenitor and stem cells. However, its related genes TET1 and TET3 provide residual enzymatic activity, sufficient to facilitate the survival of these progenitor cells harbouring cancerous mutations, thereby promoting the spread of the cancer, even when TET2 is inactive.

In their study, the research team designed TETi76 to replicate and amplify the effects of a natural molecule called 2-hydroxyglutarate (2HG), which inhibits the enzymatic activity of TET genes. They hoped to selectively eliminate TET2 mutant leukaemia cells centres by targeting their reliance on this residual DNA dioxygenase activity.

We took lessons from the natural biological capabilities of 2HG, explained Dr Babal Kant Jha, Maciejewskis collaborator from the Department of Translational Hematology & Oncology Research. We studied the molecule and rationally designed a novel small molecule, synthesised by our chemistry group headed by Dr James Phillips. Together, we generated TETi76 a similar, but more potent version capable of inhibiting not just TET2, but also the remaining disease-driving enzymatic activity of TET1 and TET3.

The researchers studied TETi76s effects in both preclinical disease and xenograft models (where human cancer cells are implanted into preclinical models). In both models, treatment with the novel TET inhibitor suppressed the clonal evolution of TET2 mutant cells.

While the team cautioned that additional studies would be critical to investigate the small molecules cancer-fighting capabilities in patients, Dr Jha said we are optimistic about our results, which show not just that TETi76 preferentially restricts the growth and spread of cells with TET2 mutations, but also gives survival advantage to normal stem and progenitor cells.

Read more here:
Novel class of targeted cancer therapies could treat myeloid leukaemias - Drug Target Review

Bone Marrow Stem Cells Comments Off on Novel class of targeted cancer therapies could treat myeloid leukaemias – Drug Target Review | December 16th, 2020