bcl11a sickle cell disease

“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. “We’re collaborating with several colleagues on exploratory assays to accomplish this,” she said, adding that the work is ongoing.

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 … “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. 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.

They did not find any grade 3 or 4 adverse events linked with mobilization, collection, or infusion.

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“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. Her coauthors reported disclosures related to Alerion Biosciences, Novartis, Orchard Therapeutics, Roche, AstraZeneca, and bluebird bio, among others.

In addition, there were no AEs related to the medicinal product. The patients are currently 7, 9, and 17 months post infusion. “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.”.

The modified cells were then infused into patients. 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. As of data presentation, 8 patients were enrolled in the trial.

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.

SOURCE: Esrick EB et al. Williams believes the BCL11A-based approach to gene therapy for sickle cell disease will substantially increase the ratio of non-sickling versus sickling hemoglobin. Presented at the 2019 ASH Annual Meeting, December 10, 2019; Orlando, FL.

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. Prior to infusion, there were no grade ≥3 adverse events (AEs) associated with mobilization or collection, she added. 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.

All rights reserved. MDedge: Keeping You Informed. Gene therapy treatment also appeared to be associated with “consistent and substantial induction” of HbF. Saving You Time. Contact Us | Terms of Service | Privacy Policy. See more with MDedge!

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“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. 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.

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. Copyright © 2020 by American Society of Hematology, Focus on Classical Hematology (Volume 6, Issue 12.1). 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. 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.

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 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. “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.

Abstract LBA-5. © 2020 MJH Life Sciences and HCPLive.

“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).”. 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. No patients have required transfusion, except one with severe underlying vascular disease for whom post–gene therapy transfusions were planned, she said.

In a 3-patient study presented at ASH, investigators believe they have found a therapeutic target to cure sickle cell disease. This issue dives into the FDA's expedited review pathways, the progress and setbacks in gene therapy for hemophilia, and more. The increase in HbF translated to improvement in severity of SCD, she noted.

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