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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. SOURCE: Esrick EB et al. 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. 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. Abstract #LBA-5. 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. “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. 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. Dr. Esrick described BCH-BB694, a lentiviral vector encoding a BCL11A-targeting small hairpin RNA embedded in a microRNA scaffold (shmiR). The total Hb remained stable in both untransfused subjects, with evidence of reduced hemolysis by reticulocyte count and LDH. See our Other Publications. Dr. Esrick described BCH-BB694, a lentiviral vector encoding a BCL11A-targeting small hairpin RNA embedded in a microRNA scaffold (shmiR). Following gene therapy, treated patients have had no instances of vaso-occlusive pain crises, respiratory events, or neurologic events. They did not find any grade 3 or 4 adverse events linked with mobilization, collection, or infusion. 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. MDedge: Keeping You Informed. “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).”. Unauthorized use prohibited. 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. All rights reserved. The modified cells were then infused into patients. 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. They also plan to conduct the next phase 2 or 3 study at multiple sites. 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. 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. ASH 2019. 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. Ultimately, the study points to a potential cure for sickle cell. Prior to infusion, there were no grade ≥3 adverse events (AEs) associated with mobilization or collection, she added. 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. 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. Saving You Time. Her coauthors reported disclosures related to Alerion Biosciences, Novartis, Orchard Therapeutics, Roche, AstraZeneca, and bluebird bio, among others. “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. Most patients had genotype HbSS disease and participant ages ranged from 7 to 36. “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. Also, no patient required transfusions, except in one patient with severe underlying neurovascular disease who was planned to continue transfusions after gene therapy.

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