BCL11A inhibition through posttranscriptional gene silencing may help to treat some patients with sickle cell disease, according to the results of a study published The New England Journal of Medicine.
Sickle cell disease, which affects as many as 100,000 patients in the United States, is characterized by a single E6V missense mutation in the beta globin gene (HBB). Although matched donor allogeneic hematopoietic stem cell transplantation is curative in more than 90% of cases, some patients are ineligible or lack an available matched sibling. When left untreated, the disease can cause hemolytic anemia, pain, and organ damage.
Erythrocyte fetal hemoglobin (HbF) levels have been shown to directly affect sickle cell disease course. The BCL11A gene, which has been linked with repression of HbF production in adult erythrocytes, appeared to be a promising therapeutic target in mouse models.
For this open-label pilot study (ClinicalTrials.gov Identifier: NCT03282656), researchers evaluated whether BCH-BB694 gene therapy is a safe and effective treatment option for patients with sickle cell disease. The treatment involves transfusing autologous CD34+ cells transduced with a lentiviral vector that encodes a short hairpin RNA targeting BCL11A mRNA embedded in a microRNA (shmiR).
Overall, 6 patients have continued follow-up for at least 6 months (median, 18 months) after receiving BCH-BB694. At the most recent follow-up, evaluable patients had robust and stable HbF induction. HbF was also distributed in red cells (F cell range [reported as a percentage of nontransfused red cells], 58.9%-93.6%). HbF per F cell ranged from 9.0 to 18.6 pg.
Symptoms and complaints of sickle cell disease were, moreover, either reduced or entirely absent over the course of follow-up. No cases of vaso-occlusive crisis, acute chest syndrome, or stroke were reported after treatment initiation.
No adverse event of grade 3 or worse was linked with treatment mobilization, collection, or infusion.
“On the basis of current HbF levels, percentage of F-cells, and HbF per F-cell, we predict that the patients in this study will have protection from sickling to prevent or significantly ameliorate both acute and chronic complications of sickle cell disease,” the authors wrote. “Additional follow-up will clarify the long-term effects.”
Disclosures: Some authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.
Esrick EB, Lehmann LE, Biffi A, et al. Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease. N Engl J Med. 2021;384(3):205-215. doi:10.1056/NEJMoa2029392