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Conference | American Society of Hematology. 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.”. All rights reserved. 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 authors report relationships with bluebird bio, which provided support for this trial. 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. 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. 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. Presented at the 2019 ASH Annual Meeting, December 10, 2019; Orlando, FL. 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. 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. 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. 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. 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 addition, there were no AEs related to the medicinal product. Conflict-of-interest disclosure: J.F.C. Copyright © 2020 by American Society of Hematology, Focus on Classical Hematology (Volume 6, Issue 12.1). In this pilot study, investigators evaluated the approach of knocking down BCL11A using RNA interference to induce gamma-globin expression with BCH-BB694. 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. “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. ASH 2019. Williams said the current plan is to extend the current pilot trial to 15 subjects, while adding additional biomarkers. “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. 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. 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 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. As of data presentation, 8 patients were enrolled in the trial. 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. “We’re collaborating with several colleagues on exploratory assays to accomplish this,” she said, adding that the work is ongoing. 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. BCL11A regulates the fetal-adult hemoglobin switch by repressing expression at gamma (y)-globin locus, representing a potential therapeutic target for sickle cell. Esrick EB, Achebe M, Armant M, et al. See our Other Publications. “The transcription factor BCL11A is a strong repressor of gamma-globin, making it an appealing target for fetal hemoglobin induction.”. The modified cells were then infused into patients. Williams believes the BCL11A-based approach to gene therapy for sickle cell disease will substantially increase the ratio of non-sickling versus sickling hemoglobin. Copyright  © 2020 Frontline Medical Communications Inc., Parsippany, NJ, USA. Autologous CD34+ cells were collected by plerixafor mobilization and then transduced ex vivo with the BCH-BB694 shmiR lentiviral vector. 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. 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 … Which provided support for this trial as of data presentation, 8 patients were in..., there were no grade ≥3 adverse events ( AEs ) associated with “ and... With “ consistent and substantial induction ” of HbF induce gamma-globin expression with BCH-BB694 no have... 2019 ASH Annual Meeting, December 10, 2019 ; Orlando, FL, treated patients have had instances! 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