bcl11a sickle cell disease

See more with MDedge! 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. Most patients had genotype HbSS disease and participant ages ranged from 7 to 36. 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. 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. In a 3-patient study presented at ASH, investigators believe they have found a therapeutic target to cure sickle cell disease. They also plan to conduct the next phase 2 or 3 study at multiple sites. The results of this ongoing study were presented by Erica Esrick, MD, from Boston Children’s Hospital, as a late-breaking abstract at the 2019 ASH Annual Meeting. 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. No patients have required transfusion, except one with severe underlying vascular disease for whom post–gene therapy transfusions were planned, she said.

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 … 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. 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.

The total Hb remained stable in both untransfused subjects, with evidence of reduced hemolysis by reticulocyte count and LDH. Dr. Esrick described BCH-BB694, a lentiviral vector encoding a BCL11A-targeting small hairpin RNA embedded in a microRNA scaffold (shmiR). Prior to infusion, there were no grade ≥3 adverse events (AEs) associated with mobilization or collection, she added. “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.

Dr. Esrick described BCH-BB694, a lentiviral vector encoding a BCL11A-targeting small hairpin RNA embedded in a microRNA scaffold (shmiR). Abstract #LBA-5. After gene therapy, the treated patients have not experienced any instances of vaso-occlusive crises, respiratory events, or neurologic events. The calculated average HbF per F cell was greater than 10 pg in all subjects and a quantitative single cell HbF flow analysis showed the majority of F cells had greater than 4 pg F/cell.

Her coauthors reported disclosures related to Alerion Biosciences, Novartis, Orchard Therapeutics, Roche, AstraZeneca, and bluebird bio, among others. All rights reserved. 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.

Autologous CD34+ cells were collected by plerixafor mobilization and then transduced ex vivo with the BCH-BB694 shmiR lentiviral vector.

At the latest follow-up (which ranged from 1 to 18 months post–gene therapy), total HbF levels had increased to between 23.8% and 42.8%, and remained stable, Dr. Esrick said. Rather than interfering with BCL11A, these approaches are introducing genes that encode fetal hemoglobin itself or a corrected beta hemoglobin that doesn’t sickle.

In this pilot study, investigators evaluated the approach of knocking down BCL11A using RNA interference to induce gamma-globin expression with BCH-BB694. There may soon be a cure for sickle cell disease. 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. Abstract LBA-5.

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. How Common Is Venous Thromboembolism in Patients Hospitalized With COVID-19? Copyright  © 2020 Frontline Medical Communications Inc., Parsippany, NJ, USA. Williams believes the BCL11A-based approach to gene therapy for sickle cell disease will substantially increase the ratio of non-sickling versus sickling hemoglobin.

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