bcl11a sickle cell disease


Presented at the 2019 ASH Annual Meeting, December 10, 2019; Orlando, FL. 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. “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. 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. Following gene therapy, treated patients have had no instances of vaso-occlusive pain crises, respiratory events, or neurologic events. They also plan to conduct the next phase 2 or 3 study at multiple sites. 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. 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. 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… 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 … Esrick EB, Achebe M, Armant M, et al. © 2020 MJH Life Sciences and HCPLive. Dr. Esrick reported having no disclosures. Abstract LBA-5. They did not find any grade 3 or 4 adverse events linked with mobilization, collection, or infusion. 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. BCH-BB694 is a lentiviral vector (LVV) encoding a shRNA targeting BCL11A embedded in a microRNA scaffold allowing erythroid-specific knockdown to induce y-globin expression and concomitantly and coordinately repress β-sickle globin expression. The remaining authors declare no competing financial interests. 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, according to findings from a small pilot study. MDedge: Keeping You Informed. Prior to infusion, there were no grade ≥3 adverse events (AEs) associated with mobilization or collection, she added. Also, no patient required transfusions, except in one patient with severe underlying neurovascular disease who was planned to continue transfusions after gene therapy. The authors report relationships with bluebird bio, which provided support for this trial. Patients also appeared to be producing high average amounts of HbF per F cell (erythrocytes that produce HbF), with percentages of HbF per F cell ranging from 37.4% to 62.1%. “We’re collaborating with several colleagues on exploratory assays to accomplish this,” she said, adding that the work is ongoing. Dr. Esrick described BCH-BB694, a lentiviral vector encoding a BCL11A-targeting small hairpin RNA embedded in a microRNA scaffold (shmiR). is a consultant to Adventrx Corporation and has received an honorarium and travel expenses from Adventrx Corporation for assisting them with a possible clinical trial of an agent to treat vasooclusive crisis in sickle cell disease. 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. 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. 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. Williams said the current plan is to extend the current pilot trial to 15 subjects, while adding additional biomarkers. The 2 untransfused subjects produced 70% F-cells in peripheral blood at 3 and 5 months and remained stabled until the last point assayed—15 months and 7.5 months. “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. This issue dives into the FDA's expedited review pathways, the progress and setbacks in gene therapy for hemophilia, and more. Cell products were manufactured for 6 patients, Dr. Esrick reported, with cell doses of 3.3 to 8.3 million CD34-positive cells/kg and high vector copy numbers, “indicating successful manufacturing and a highly efficient vector.”. However, results from this small, single-arm pilot study will need to be validated in larger, longer-term studies. The modified cells were then infused into patients. 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. After gene therapy, the treated patients have not experienced any instances of vaso-occlusive crises, respiratory events, or neurologic events. All rights reserved. After testing and releasing the gene modified cells, the investigators infused them into the patients, who had received busulfan conditioning. BCL11A regulates the fetal-adult hemoglobin switch by repressing expression at gamma (y)-globin locus, representing a potential therapeutic target for sickle cell. 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. In a 3-patient study presented at ASH, investigators believe they have found a therapeutic target to cure sickle cell disease. See more with MDedge! Gene therapy treatment also appeared to be associated with “consistent and substantial induction” of HbF. Rather than interfering with BCL11A, these approaches are introducing genes that encode fetal hemoglobin itself or a corrected beta hemoglobin that doesn’t sickle. Knocking down BCL11A using a lentiviral vector-based approach resulted in effective induction of fetal hemoglobin and significant attenuation of the sickling phenotype, with no vector-related adverse events, investigator Erica B. Esrick, MD, of Children’s Hospital Boston, said during the meeting’s late-breaking abstracts session. BCL11A regulates the fetal-adult hemoglobin switch by repressing expression at gamma (y)-globin locus, representing a potential therapeutic target for sickle cell. The information provided is for educational purposes only. How Common Is Venous Thromboembolism in Patients Hospitalized With COVID-19? 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. No patients have required transfusion, except one with severe underlying vascular disease for whom post–gene therapy transfusions were planned, she said. In addition, there were no AEs related to the medicinal product. 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. Most patients had genotype HbSS disease and participant ages ranged from 7 to 36. 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. “The advantage of this approach is that it harnesses the physiologic switch machinery, simultaneously increasing fetal hemoglobin and decreasing sickle hemoglobin, thus maintaining the alpha to beta globin ratio in the cell,” she said. There may soon be a cure for sickle cell disease. “The advantage of this over other approaches we think is that the defective sickling beta globin is down regulated at the same time that the fetal hemoglobin is induced and the ratio of alpha to beta globin chains remained balanced,” Williams said. In this pilot study, investigators evaluated the approach of knocking down BCL11A using RNA interference to induce gamma-globin expression with BCH-BB694. See our Other Publications. All rights reserved. “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. The increase in HbF translated to improvement in severity of SCD, she noted. 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. Williams believes the BCL11A-based approach to gene therapy for sickle cell disease will substantially increase the ratio of non-sickling versus sickling hemoglobin. SOURCE: Esrick EB et al. Ultimately, the study points to a potential cure for sickle cell. 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. Saving You Time. Use of this Web site is subject to the medical disclaimer. 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. Autologous CD34+ cells were collected by plerixafor mobilization and then transduced ex vivo with the BCH-BB694 shmiR lentiviral vector. 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. Total fetal hemoglobin has increased and remained stable at between 23% and 43% for the five patients, who are producing “stably high” average amounts of fetal hemoglobin per F cell, at 10 to 16 picograms of fetal hemoglobin per cell, while 37% to 62% of the F cells’ total hemoglobin is fetal hemoglobin, she added. This level is believed to prevent sickling under physiological oxygen saturation. “In conclusion, these data demonstrate successful and sustained engraftment in three adult patients treated with LVV-delivered shmiR technology targeting BCL11A.”.

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