Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 disruption of the HBG1 and HBG2 gene promoters may induce the production of fetal hemoglobin in patients with severe sickle cell disease (SCD) and yield sustained clinical improvement, according to an article published in The New England Journal of Medicine.
The aim of this multicenter, phase 1/2 clinical study was to evaluate the safety and adverse effect profile of OTQ923 in a cohort of patients with severe SCD.
“Elevated fetal hemoglobin levels in red cells protect against complications of sickle cell disease. OTQ923, a CRISPR-Cas9-edited CD34+ hematopoietic stem- and progenitor-cell (HSPC) product, has a targeted disruption of the HBG1 and HBG2 (γ-globin) gene promoters that increase fetal hemoglobin expression in the red-cell progeny,” Sharma and colleagues explained.
The researchers initially performed a tiling CRISPR-Cas9 screen of the HBG1 and HBG2 promoters by electroporating CD34+ cells obtained from healthy donors with Cas9 complexed with 1 of 72 guide RNAs.
Read more about SCD experimental therapies
They then evaluated the fraction of fetal hemoglobin-immunostaining erythroblasts (F cells) in erythroid-differentiated progeny and used the guide RNA with the highest level of F cells for clinical development.
According to the results, the preclinical experiments showed the ability of CD34+ HSPCs, which were edited with CRISPR-Cas9 and guide RNA-68, to induce on-target editing with no off-target mutations and yield high levels of fetal hemoglobin upon in vitro differentiation or xenotransplantation into immunodeficient mice.
Three patients were given autologous OTQ923 after myeloablative conditioning and followed for 6 to 18 months. The researchers found engraftment and sustained induction of fetal hemoglobin, which was broadly distributed across their red blood cells. All three participants experienced significant clinical improvement.
SCD, caused by a defect in the β-globin subunit of adult hemoglobin, is marked by the production of deformed red blood cells prone to hemolysis and vaso-occlusion, which may result in progressive organ damage and even premature death.
Reference
Sharma A, Boelens JJ, Cancio M, et al. CRISPR-Cas9 editing of the HBG1 and HBG2 promoters to treat sickle cell disease. N Engl J Med. Published online August 31, 2023. doi:10.1056/NEJMoa2215643
