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For patients with sickle cell disease (SCD), extracting marrow cells and transforming them to promote generation of fetal hemoglobin instead of defective hemoglobin could have durable clinical activity and be tolerable in treating SCD, according to late-breaking data from an ongoing phase 1 trial presented at the 61st American Society of Hematology (ASH) Annual Meeting in Orlando, Florida.
This treatment used a shmiR-lentiviral vector to target BCL11A specifically in erythrocytes, a protein that inhibits gammaglobin. Gammaglobin regulates the transition from fetal to adult hemoglobin, and the lentiviral approach knocks it down. By extracting CD34+ marrow cells and transforming them with the vector, they could then be transplanted into target knocking down BCL11A, allowing for the production of fetal hemoglobin.
With follow-up ranging from 1 to 18 months, results from the first 5 of 15 planned patients with SCD who underwent the transformation showed the patients experienced higher levels of fetal hemoglobin after undergoing the procedure, rising from 0% to 10% at baseline to 75% within 6 months of transplant. Mean fetal hemoglobin levels at the most recent timepoint of measurement ranged from 37.4% to 62.1%.
Though this study did not have formal end points of clinical efficacy, no patients experienced vaso-occlusive pain crisis following treatment.
Nonlaboratory grade 3 or higher adverse events (AEs) included nausea, febrile neutropenia, mucositis, and vomiting. Serious AEs occurring after infusion included influenza, recurrent priapism, and nonsickle ankle pain. After evaluation, it was determined that the ankle pain was due to a sprained ankle and was not related to the treatment. These AEs are common to the conditioning regimen needed for the transplant and were similar to AEs commonly experienced by patients with other hematologic malignancies undergoing stem cell transplant.
No patients experienced neurologic or respiratory events.
Only 1 patient received transfusions during the study, and the transfusions were preplanned because of vascular damage that existed prior to enrollment in the trial. Prior to transplant, the patient had received transfusions every month. After transplant, the patient was able to receive transfusion every other month.
Because this treatment does not completely abrogate the generation of sickled erythrocytes, some disease manifestations can continue to occur. Nonetheless, these results indicate this approach results in “significant attenuation of sickling phenotype,” the researchers noted.
- Esrick EB, Achebe M, Armant M, et al. 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. Oral presentation at: 2019 ASH Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL. Abstract LBA5.