1. In this randomized controlled trial, infusion of OTQ923 disrupted inhibitory HBG1 and HBG2 promoter regions of the gamma-globin gene.
2. This disruption resulted in sustained production of fetal hemoglobin and improved symptoms of severe sickle cell disease (SCD).
Evidence Rating Level: 2 (Good)
Study Rundown: SCD is caused by mutations disrupting the function of the beta-globin subunit of adult hemoglobin, leading to sickle hemoglobin that is prone to deformation and dysfunction under hypoxia. This can result in anemia, pain crises, organ damage, and high mortality. Symptoms arise during infancy as fetal hemoglobin transitions to adult hemoglobin. Current therapies aim at promoting fetal hemoglobin production but are only partially effective. The only curative approach is allogeneic transplantation, which is limited and carries risks of immunologic complications. The current study investigated the effects of OTQ923, a personalized clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-edited CD34+ hematopoietic stem cell (HSC) product, derived from a patient’s own blood which had its HBG1 and HBG2 inhibitory promoter regions within the gamma-globin gene before being infused back into patients following myeloablation. OTQ923 resulted in sustained production of fetal hemoglobin and ameliorated SCD symptoms among the three study participants through to 18 months. Preclinical experiments found no off-target effects. Despite the small sample size intrinsic to gene therapy trials, these results demonstrated the potential of OTQ923 in offering durable effective treatment for SCD.
In-Depth [randomized controlled trial]: The current study is an ongoing clinical trial to investigate the effects of OTQ923, an autologous CRISPR-Cas9-edited CD34+ HSC product, in the management of severe SCD. Patients between 18 and 40 years of age with severe SCD, as defined by prespecified criteria, were eligible for inclusion. The guide RNA sequences for HBG1 and HBG2 promoters (gRNA-68) were identified through unbiased CRISPR-Cas9 screening of CD34+ cells from healthy donors. Three participants received red-cell exchange transfusions prior to collections of CD34+ HSC via apheresis. The apheresis product was further enriched for CD34+ cells and electroporated with the CRISPR-Cas9 gRNA-68 ribonucleoprotein complex to repress HBG1 and/or HBG2 promoters to produce OTQ923. The time to neutrophil and platelet engraftments, fetal hemoglobin expression, and on-target edits were the main outcomes of interest. Three participants had been treated at the time of reporting. All three had severe SCD with recurrent vaso-occlusive crises being treated with hydroxyurea and regular red-cell exchange transfusions. Their fetal hemoglobin levels were less than 5%. Fetal hemoglobin levels ranged from 19.0-26.8% and the proportions of red blood cells carrying fetal hemoglobin ranged from 69.7-87.7% by the end of follow-up. Adverse events were adjudicated to be related to busulfan myeloablation or underlying SCD and none associated with OTQ923. No evidence of myelodysplasia was reported. SCD clinical manifestations improved, as demonstrated by the reduced symptom incidence, hematologic indices, and hemolysis. In summary, these results showed that OTQ923 and similar approaches utilizing CRISPR-Cas9 could offer safe and effective management for patients with severe SCD.
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