See our Other Publications. 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%. 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. Validated assays at the single-cell level are needed to better understand the effect of this gene therapy and eventually compare it to other therapeutic approaches in sickle cell disease, according to Dr. Esrick. “The transcription factor BCL11A is a strong repressor of gamma-globin, making it an appealing target for fetal hemoglobin induction.”. 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. Gene therapy treatment also appeared to be associated with “consistent and substantial induction” of HbF. The total Hb remained stable in both untransfused subjects, with evidence of reduced hemolysis by reticulocyte count and LDH. Unauthorized use prohibited. MDedge: Keeping You Informed. Autologous CD34+ cells were collected by plerixafor mobilization and then transduced ex vivo with the BCH-BB694 shmiR lentiviral vector. 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 this pilot study, investigators evaluated the approach of knocking down BCL11A using RNA interference to induce gamma-globin expression with BCH-BB694. Ultimately, the study points to a potential cure for sickle cell. 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. 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. Abstract LBA-5. 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. “At the 3-month time point before re-starting transfusions, the subject with moyamoya had a pre-transfusion Hb of 11 g/dL with 76% of non-transfused cells containing on average 17pg F/F cell,” the authors wrote. 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. Saving You Time. Copyright © 2020 by American Society of Hematology, Focus on Classical Hematology (Volume 6, Issue 12.1). No patients have required transfusion, except one with severe underlying vascular disease for whom post–gene therapy transfusions were planned, she said. Presented at the 2019 ASH Annual Meeting, December 10, 2019; Orlando, FL. 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. Dr. Esrick described BCH-BB694, a lentiviral vector encoding a BCL11A-targeting small hairpin RNA embedded in a microRNA scaffold (shmiR). 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 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. 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. “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. “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. After testing and releasing the gene modified cells, the investigators infused them into the patients, who had received busulfan conditioning. The patients are currently 7, 9, and 17 months post infusion. 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. BCL11A regulates the fetal-adult hemoglobin switch by repressing expression at gamma (y)-globin locus, representing a potential therapeutic target for sickle cell. Her coauthors reported disclosures related to Alerion Biosciences, Novartis, Orchard Therapeutics, Roche, AstraZeneca, and bluebird bio, among others. All rights reserved. In addition, there were no AEs related to the medicinal product. 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. The modified cells were then infused into patients. 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. This issue dives into the FDA's expedited review pathways, the progress and setbacks in gene therapy for hemophilia, and more. ASH 2019. 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. Use of this Web site is subject to the medical disclaimer. 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. Rather than interfering with BCL11A, these approaches are introducing genes that encode fetal hemoglobin itself or a corrected beta hemoglobin that doesn’t sickle. They also plan to conduct the next phase 2 or 3 study at multiple sites. The remaining authors declare no competing financial interests. 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 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. BCL11A regulates the fetal-adult hemoglobin switch by repressing expression at gamma (y)-globin locus, representing a potential therapeutic target for sickle cell. Dr. Esrick reported having no disclosures. They did not find any grade 3 or 4 adverse events linked with mobilization, collection, or infusion. 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. “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).”. © 2020 MJH Life Sciences™ and HCPLive. Conference | American Society of Hematology. All rights reserved. The information provided is for educational purposes only. 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. SOURCE: Esrick EB et al. Leukemia, Myelodysplasia, Transplantation, ASH releases guidelines on managing cardiopulmonary and kidney disease in SCD, Clinical Advances in Thrombocytopenia Series, Second-Line Non-Small Cell Lung Cancer: Follow-Up Survival Data with Immunotherapy, Nurse Practitioners / Physician Assistants. Most patients had genotype HbSS disease and participant ages ranged from 7 to 36. Conflict-of-interest disclosure: J.F.C. “CL11A protein levels evaluated by immunoblot in subject BCL002 at 30 days (PB) and 6 months (BM) post-infusion showed highly effective and selective knockdown of BCL11A in erythroid progenitors with no reduction in BCL11A expression in B lymphoid cells,” the authors wrote. BCH-BB694 is an investigational gene therapy product manufactured by embedding a BCL11A-targeting structure in patients’ autologous CD34-positive cells using a 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. Esrick EB, Achebe M, Armant M, et al. 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. 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. 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. As of data presentation, 8 patients were enrolled in the trial. “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. 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… In a 3-patient study presented at ASH, investigators believe they have found a therapeutic target to cure sickle cell disease. All rights reserved. “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.

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