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. Copyright  © 2020 Frontline Medical Communications Inc., Parsippany, NJ, USA.

Gene therapy treatment also appeared to be associated with “consistent and substantial induction” of HbF. SOURCE: Esrick EB et al.

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. 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… “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. Conference | American Society of Hematology.

“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. 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. 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.

Development of the gene therapy described by Dr. Esrick involves mobilization of the patient’s peripheral stem cells using plerixafor, followed by selection of CD34+ cells that were transduced with the shmiR lentiviral vector, followed by infusion of gene modified cells into the patient after a busulfan conditioning regimen. All rights reserved. © 2020 MJH Life Sciences and HCPLive. Abstract LBA-5.

“In conclusion, these data demonstrate successful and sustained engraftment in three adult patients treated with LVV-delivered shmiR technology targeting BCL11A.”. Most patients had genotype HbSS disease and participant ages ranged from 7 to 36. They also plan to conduct the next phase 2 or 3 study at multiple sites. Following gene therapy, treated patients have had no instances of vaso-occlusive pain crises, respiratory events, or neurologic events. Williams believes the BCL11A-based approach to gene therapy for sickle cell disease will substantially increase the ratio of non-sickling versus sickling hemoglobin.

In addition, there were no AEs related to the medicinal product.

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. “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).”.

How Common Is Venous Thromboembolism in Patients Hospitalized With COVID-19? Prior to infusion, there were no grade ≥3 adverse events (AEs) associated with mobilization or collection, she added. 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 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. 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. In a 3-patient study presented at ASH, investigators believe they have found a therapeutic target to cure sickle cell disease. “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. Conflict-of-interest disclosure: J.F.C. As of data presentation, 8 patients were enrolled in the trial. “The transcription factor BCL11A is a strong repressor of gamma-globin, making it an appealing target for fetal hemoglobin induction.”.

They did not find any grade 3 or 4 adverse events linked with mobilization, collection, or infusion. Abstract #LBA-5. 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.

“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.

Ultimately, the study points to a potential cure for sickle cell. Presented at the 2019 ASH Annual Meeting, December 10, 2019; Orlando, FL.

However, results from this small, single-arm pilot study will need to be validated in larger, longer-term studies. 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.

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