CRISPR gene therapy has demonstrated increased total haemoglobin levels and sustained fetal haemoglobin production in patients with severe sickle cell disease, according to early phase clinical data.
CRISPR Gene Therapy Outcomes in Sickle Cell Disease
Renizgamglogene autogedtemcel is an investigational clustered regularly interspaced short palindromic repeats Cas12a gene edited autologous haematopoietic stem cell therapy designed to reactivate fetal haemoglobin production. This is achieved through disruption of BCL11A binding sites in the HBG1 and HBG2 promoters. In a phase 1–2 multicentre open label study, 28 patients with severe sickle cell disease aged 12–50 years received a single infusion following myeloablative conditioning with busulfan. All participants had experienced at least two severe vaso occlusive events annually over the previous 2 years.
Haematological And Engraftment Findings
At a median follow up of 9.5 months, 27 of 28 patients achieved neutrophil and platelet engraftment. Median time to neutrophil engraftment was 23 days, with platelet engraftment occurring at 25 days. Among 18 patients with at least 6 months of follow up data, mean total haemoglobin increased from 9.8±1.7 g per decilitre at baseline to 13.8±1.9 g per decilitre. Mean fetal haemoglobin rose from 2.5±2.5% to 48.1±3.2% by month 6, with both measures maintained thereafter. These findings indicate effective gene editing and sustained haematological improvement.
Clinical Events and Safety Profile
Only one patient experienced two severe vaso occlusive events following infusion, while the remaining 27 patients reported no such events during follow up. Adverse events were consistent with those expected after busulfan based conditioning and autologous haematopoietic stem cell transplantation. Monitoring included engraftment, haemoglobin metrics, allelic editing levels, and safety outcomes over a planned 24 month period. However, the study was terminated early following reassessment of clinical development priorities, and the reported analysis was not prespecified.
Overall, CRISPR gene therapy with renizgamglogene autogedtemcel was associated with normalisation of total haemoglobin and substantial increases in fetal haemoglobin, alongside a marked reduction in vaso occlusive events. These data support further investigation of this gene editing approach in severe sickle cell disease.
Reference
Hanna R et al. CRISPR-Cas12a gene editing of HBG1 and HBG2 promoters to treat sickle cell disease. N Engl J Med. 2026;394:1281-91.
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