CRISPR-Cas9 Editing of the HBG1 and HBG2 Promoters to Treat Sickle Cell Disease.
In a phase 1-2 study, OTQ923, an autologous CRISPR-Cas9-edited hematopoietic stem-cell product disrupting the HBG1 and HBG2 (gamma-globin) gene promoters, produced durable increases in fetal hemoglobin in three participants with severe sickle cell disease.
Background
Sickle cell disease results from a defect in the beta-globin subunit of adult hemoglobin; under hypoxic conditions sickle hemoglobin polymerizes, producing deformed red cells that hemolyze and cause vaso-occlusion, progressive organ damage, and early death. Elevated fetal hemoglobin protects against complications, providing a rationale for reactivating gamma-globin expression by editing the HBG1 and HBG2 promoters.
Study design
Investigators performed a tiling CRISPR-Cas9 screen of the HBG1 and HBG2 promoters using 72 guide RNAs in CD34+ cells from healthy donors, selecting the guide (gRNA-68) yielding the highest fraction of fetal-hemoglobin-positive erythroblasts for clinical development as OTQ923. Three participants with severe sickle cell disease received autologous OTQ923 after myeloablative conditioning and were followed for 6 to 18 months.
Key findings
In preclinical work, CD34+ cells edited with gRNA-68 showed sustained on-target editing with no detected off-target mutations and produced high levels of fetal hemoglobin after in vitro differentiation or xenotransplantation into immunodeficient mice. In the three treated participants, the edited stem-cell product engrafted and was associated with durable, pancellular fetal hemoglobin induction over the reported follow-up period.
Clinical implications
These early results support targeted disruption of the gamma-globin gene promoters as a gene-editing strategy to raise fetal hemoglobin in severe sickle cell disease. As a small phase 1-2 study with limited follow-up, the findings establish proof of concept and an initial safety signal, while longer-term and larger studies are needed to confirm durability and clinical benefit.
Category
Research
Source
N Engl J Med
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