bcl11a sickle cell disease

The single-center pilot and feasibility study, originally designed to include a total of seven patients, now has an expanded enrollment goal of 15 patients, and a multicenter phase 2/3 study is planned that will enroll a larger group of patients with sickle cell disease, according to Dr. Esrick. See our Other Publications. In addition, there were no AEs related to the medicinal product. Unauthorized use prohibited. However, results from this small, single-arm pilot study will need to be validated in larger, longer-term studies. The authors report relationships with bluebird bio, which provided support for this trial. All rights reserved. BCL11A represents a promising target in sickle cell disease because of its regulation of the fetal-adult hemoglobin switch at the gamma-globin locus, investigators said in their late-breaking study abstract. The approved open-label study was not randomized and held at a single center, where 3 adult patients were enrolled with more than 6 months of follow up. Her coauthors reported disclosures related to Alerion Biosciences, Novartis, Orchard Therapeutics, Roche, AstraZeneca, and bluebird bio, among others. Contact Us | Terms of Service | Privacy Policy. Ultimately, the study points to a potential cure for sickle cell. The increase in HbF translated to improvement in severity of SCD, she noted. ORLANDO – A gene therapy approach that targets a major repressor of fetal hemoglobin appears to be acceptably safe and to mitigate the pathology of sickle cell disease among the five patients infused so far, an investigator reported at the annual meeting of the American Society of Hematology. In a 3-patient study presented at ASH, investigators believe they have found a therapeutic target to cure sickle cell disease. The patients, who range in age from 12 to 26 years, are producing and maintaining very high numbers of F cells, or erythrocytes with measurable fetal hemoglobin, she said. All rights reserved. All 3 of the adult subjects, which were between 21-26 years old, demonstrated neutrophil engraftment on day +22 with adverse events consistent with busulfan conditioning. Abstract #LBA-5. They did not find any grade 3 or 4 adverse events linked with mobilization, collection, or infusion. Following infusion of modified cells, the vector copy number was found to be stable at 6 months, indicating effective knockdown of BCL11A at the protein level. Rather than interfering with BCL11A, these approaches are introducing genes that encode fetal hemoglobin itself or a corrected beta hemoglobin that doesn’t sickle. Autologous CD34+ cells were collected by plerixafor mobilization and then transduced ex vivo with the BCH-BB694 shmiR lentiviral vector. Conflict-of-interest disclosure: J.F.C. In this pilot study, investigators evaluated the approach of knocking down BCL11A using RNA interference to induce gamma-globin expression with BCH-BB694. BCL11A regulates the fetal-adult hemoglobin switch by repressing expression at gamma (y)-globin locus, representing a potential therapeutic target for sickle cell. MDedge: Keeping You Informed. These results suggest that BCL11A is an effective molecular target for patients with SCD and that targeting the factor with the shmiR vector leads to effective HbF induction, the authors concluded. Per study protocol, participants underwent stem cell mobilization with plerixafor and CD34-positive cells were collected for ex vivo transduction; during transduction, patients received myeloablative conditioning with busulfan. The patients are currently 7, 9, and 17 months post infusion. © 2020 MJH Life Sciences and HCPLive. Because of a pre-existing moyamoya, 1 of the patients resumed red cell transfusions at 3 months using a pre-defined conservative trigger value of 40% sickle Hb in whole blood. Dr. Esrick described BCH-BB694, a lentiviral vector encoding a BCL11A-targeting small hairpin RNA embedded in a microRNA scaffold (shmiR). Now, new research led by Howard Hughes Medical Institute (HHMI) investigator Stuart H. Orkin of Children’s Hospital Boston, Dana Farber Cancer Institute, and Harvard Medical School shows that silencing a protein known as BCL11A can reactivate fetal hemoglobin production in adult mice and effectively reverses sickle cell disease. This level is believed to prevent sickling under physiological oxygen saturation. “In our treated patients, we’ve seen a consistent and substantial induction in fetal hemoglobin,” Dr. Esrick said, noting that the longest follow-up to date for the five treated patients is now 18 months. In a press briefing at ASH on the late-breaking trials, David Williams, MD, Boston Children’s Hospital, explained how this trial shows promise in curing sickle cell disease. “We’re collaborating with several colleagues on exploratory assays to accomplish this,” she said, adding that the work is ongoing. “The exciting thing is that there are now multiple ways of going at this previously incurable disease,” Dr. Brodsky, who was not involved in the research, said during a press conference. Esrick EB, Achebe M, Armant M, et al. Also, no patient required transfusions, except in one patient with severe underlying neurovascular disease who was planned to continue transfusions after gene therapy. Following gene therapy, treated patients have had no instances of vaso-occlusive pain crises, respiratory events, or neurologic events. Validation of BCL11A as therapeutic target in sickle cell disease: results from the adult cohort of a pilot/feasibility gene therapy trial inducing sustained expression of fetal hemoglobin using post-transcriptional gene silencing. Conference | American Society of Hematology. © 2020 MJH Life Sciences™ and HCPLive. How Common Is Venous Thromboembolism in Patients Hospitalized With COVID-19? “Fetal hemoglobin prevents the polymerization of sickle hemoglobin [and] pancellular distribution of fetal hemoglobin is a therapeutic goal because it protects a large proportion of cells from sickling,” Dr. Esrick explained. “For all subjects, we estimated the fraction of RBCs containing significant Hb sickle polymers and the amount of polymer in each sickled RBC at physiologic oxygen tension (where 50% of monomeric hemoglobin was oxygen saturated, or the P50).”. For the patient who required transfusion, gene therapy allowed clinicians to extend his transfusion interval from 1 to 2 months, while still maintaining a pre-transfusion sickle Hb level no higher than the level prior to infusion, Dr. Esrick added. Among 4 patients who had been followed for at least 3 months after gene therapy infusion, Hb returned to “near-normal” levels (range = 10.9-11.8 g/dL) and had substantially increased compared with baseline Hb levels. Most patients had genotype HbSS disease and participant ages ranged from 7 to 36. This issue dives into the FDA's expedited review pathways, the progress and setbacks in gene therapy for hemophilia, and more. Saving You Time. Prior to infusion, there were no grade ≥3 adverse events (AEs) associated with mobilization or collection, she added. Use of this Web site is subject to the medical disclaimer. “In conclusion, these data demonstrate successful and sustained engraftment in three adult patients treated with LVV-delivered shmiR technology targeting BCL11A.”. This new lentiviral vector “allows for delivery of a more ‘physiologic’ genetic payload and for regulated erythroid expression, avoiding the toxicity that would occur if we knocked down BCL11A in hematopoietic stem cells or B cells,” Dr. Esrick noted. Copyright  © 2020 Frontline Medical Communications Inc., Parsippany, NJ, USA. Addition of Elotuzumab Prolongs Survival in Relapsed or Refractory Myeloma, Fresh Frozen Plasma May Help Maintain Successful Pregnancy in Women With Congenital TTP, Smokeless Tobacco Linked to Subtherapeutic INR in Warfarin-Treated Patient, Evaluating the TP53 State and Its Implications for Myelodysplastic Syndromes Outcomes, MLL Associated With Worse Post-Transplant Outcomes Than Other Cytogenetic Factors, Study Examines Trends in Real-World Treatment Sequencing Patterns for CLL/SLL, Editor’s Corner: Move Over Millennials: Time to Teach Outside the Boundaries. The results of the pilot study of the shmiR vector approach, although preliminary and in need of longer follow-up, contribute to a larger body of research showing that multiple gene therapy approaches hold promise in this disease, said Robert Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School of Medicine, Baltimore. A BCL11A-targeting gene therapy in patients with sickle cell disease (SCD) led to higher levels of fetal hemoglobin (HbF) and reductions in the severity of disease… There also were not any adverse events related to the gene therapy product and vector copy number was stable in bone marrow (BM) and peripheral blood (PB) in all cell lineages during the length of the study, with the latest time point studies at 15 months and ranged from .45-2.85 copies per cell in erythroid progenitor cells. The only grade ≥3 AEs observed were related to central venous line (including thrombosis, pneumothorax, and infection). BCL11A regulates the fetal-adult hemoglobin switch by repressing expression at the gamma (γ)-globin locus (Sankaran et al., Science, 2008), and thus it represents an appealing therapeutic target for sickle cell disease (SCD).BCH-BB694 is a lentiviral vector (LVV) encoding a shRNA targeting BCL11A embedded in a microRNA scaffold (shmiR) allowing erythroid-specific knockdown to induce γ … “The results for all 3 subjects in this adult cohort showed fewer RBCs with significant Hb polymer than 2 hydroxyurea-responsive treated comparators and significantly less Hb polymer per sickled RBC than a third highly responsive hydroxyurea-treated comparator,” the authors wrote. There may soon be a cure for sickle cell disease. A team of investigators, led by Erica B. Esrick, MD, Children’s Hospital Boston, presented in a late-breaking abstract at the American Society of Hematology (ASH) 2019 a pilot and feasibility gene therapy study demonstrating the safety of an infusion of BCH-BB694-transduced autologous CD34+ cells in patients with severe sickle cell disease.

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