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.