Abstract #LBA-5.

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. 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. Esrick EB, Achebe M, Armant M, et al. Copyright  © 2020 Frontline Medical Communications Inc., Parsippany, NJ, USA.

This level is believed to prevent sickling under physiological oxygen saturation.

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 … Gene therapy treatment also appeared to be associated with “consistent and substantial induction” of HbF. How Common Is Venous Thromboembolism in Patients Hospitalized With COVID-19? 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.

Most patients had genotype HbSS disease and participant ages ranged from 7 to 36. 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.

© 2020 MJH Life Sciences™ and HCPLive. These data indicate that targeting BCL11A and/or KLF1 with ASO treatment can cause an increase in γ-globin expression that is necessary for the upregulation of fetal hemoglobin and may be used for the treatment of sickle-cell anemia and β-thalassemia. Williams said the current plan is to extend the current pilot trial to 15 subjects, while adding additional biomarkers. All rights reserved.

The only grade ≥3 AEs observed were related to central venous line (including thrombosis, pneumothorax, and infection). 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.”. No patients have required transfusion, except one with severe underlying vascular disease for whom post–gene therapy transfusions were planned, she said. Copyright © 2020 by American Society of Hematology, Focus on Classical Hematology (Volume 6, Issue 12.1). 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. They did not find any grade 3 or 4 adverse events linked with mobilization, collection, or infusion. Dr. Esrick described BCH-BB694, a lentiviral vector encoding a BCL11A-targeting small hairpin RNA embedded in a microRNA scaffold (shmiR).

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. Presented at the 2019 ASH Annual Meeting, December 10, 2019; Orlando, FL. “We’re collaborating with several colleagues on exploratory assays to accomplish this,” she said, adding that the work is ongoing. See our Other Publications. “The transcription factor BCL11A is a strong repressor of gamma-globin, making it an appealing target for fetal hemoglobin induction.”.

After gene therapy, the treated patients have not experienced any instances of vaso-occlusive crises, respiratory events, or neurologic events. 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 information provided is for educational purposes only. 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.

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The remaining authors declare no competing financial interests. Conflict-of-interest disclosure: J.F.C. 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%. 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. Ultimately, the study points to a potential cure for sickle cell. Unauthorized use prohibited. Also, no patient required transfusions, except in one patient with severe underlying neurovascular disease who was planned to continue transfusions after gene therapy. They also plan to conduct the next phase 2 or 3 study at multiple sites. 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. Following gene therapy, treated patients have had no instances of vaso-occlusive pain crises, respiratory events, or neurologic events. 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. 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. 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. “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. Use of this Web site is subject to the medical disclaimer. The patients are currently 7, 9, and 17 months post infusion. As of data presentation, 8 patients were enrolled in the trial. In addition, there were no AEs related to the medicinal product. All rights reserved. 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. 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.

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. All rights reserved. Saving You Time. 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 total Hb remained stable in both untransfused subjects, with evidence of reduced hemolysis by reticulocyte count and LDH. Autologous CD34+ cells were collected by plerixafor mobilization and then transduced ex vivo with the BCH-BB694 shmiR lentiviral vector. The modified cells were then infused into patients.

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 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. BCL11A regulates the fetal-adult hemoglobin switch by repressing expression at gamma (y)-globin locus, representing a potential therapeutic target for sickle cell. 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. “In conclusion, these data demonstrate successful and sustained engraftment in three adult patients treated with LVV-delivered shmiR technology targeting BCL11A.”. Abstract LBA-5. “The number of HbF-containing cells (F cells) was assessed by flow cytometry and the kinetics of F cell production was remarkably similar in all subjects.”.

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. 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. BCL11A regulates the fetal-adult hemoglobin switch by repressing expression at gamma (y)-globin locus, representing a potential therapeutic target for sickle cell.

The increase in HbF translated to improvement in severity of SCD, she noted. © 2020 MJH Life Sciences and HCPLive. In a 3-patient study presented at ASH, investigators believe they have found a therapeutic target to cure sickle cell disease. “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. ASH 2019. Prior to infusion, there were no grade ≥3 adverse events (AEs) associated with mobilization or collection, she added. Contact Us | Terms of Service | Privacy Policy. In this pilot study, investigators evaluated the approach of knocking down BCL11A using RNA interference to induce gamma-globin expression with BCH-BB694.

Rather than interfering with BCL11A, these approaches are introducing genes that encode fetal hemoglobin itself or a corrected beta hemoglobin that doesn’t sickle.

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