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CRISPR/Cas9-Edited Gene Therapy for Sickle Cell Disease
Gene therapy remains an attractive option for cure of sickle cell disease (SCD), as the disease is caused by a single point mutation in the beta-globin gene. This industry-funded phase 2/3 interventional study evaluated the safety and tolerability of OTQ923 — an autologous, ex vivo, CRISPR/Cas9-edited, CD34+ cellular product — in the treatment of SCD. OTQ923 prevents the fetal-to-adult hemoglobin switch by inhibiting the interaction of transcription factors with regulatory elements in the γ-globin promoters (HBG1/HBG2) that are responsible for this switch.
Three young adults with severe SCD received standard-of-care treatment with hydroxyurea and red cell exchange prior to receiving a single infusion of OTQ923. Follow-up ranged from 6 to 18 months. The key observations were as follows:
- Adequate hematopoietic stem cells (CD34+) could be mobilized after hydroxyurea was discontinued for 2 to 8 months prior to collection of stem cells.
- Successful engraftment with neutrophils and platelets occurred within the same timeframe as that of genetically unmodified CD34+ selected grafts (18 to 26 days).
- The genetically modified CD34+ cells retained normal trilineage differentiation ability.
- During follow-up, all three patients had desired hematologic parameters:
- Total hemoglobin levels ranged from 10.5 to 11.0 g/dL.
- Fetal hemoglobin as a percentage of total hemoglobin ranged from 19.0% to 26.8%.
- Fetal hemoglobin cells as a percentage of red cells ranged from 69.7% to 87.8%.
- Adverse events were related to the stem cell transplant conditioning regimen.
- Participants continued to have SCD-related complications, but at a lower rate, and did not require red cell transfusions.
- No off-target genetic events were observed.
This study shows promising short-term safety, efficacy, and durability of the CRISPR/Cas9-edited gene therapy, OTQ923, for the treatment of SCD. Of note, red cell fetal hemoglobin levels were insufficient to inhibit sickle hemoglobin polymerization completely; consequently, SCD complications could not be eradicated. Considering the outcomes and risks of stem cell transplant, disease-modifying novel therapeutics (voxelotor or pyruvate kinase activator) may be more attractive options than gene therapy.
Sharma A et al.
Title: CRISPR-Cas9 editing of the HBG1 and HBG2 promoters to treat sickle cell disease.
Source: N Engl J Med 2023 Aug 31; [e-pub]. (Abstract/FREE Full Text)