N Engl J Med
Gene-editing candidate offers ‘functional cure’ in severe sickle cell disease
sClinical takeaway: One-time gene-editing therapy candidate offers a respite from severe sickle cell disease, with marked reductions in pain crises and normalization of hemoglobin.
Gene therapies are becoming an established pathway to eliminate crises in severe sickle cell disease. There are two FDA-approved therapies already here, with further data for a third candidate now reported. But the costs and logistics remain largely insurmountable for patients.
A single infusion of renizgamglogene autogedtemcel (reni-cel), an autologous CRISPR-Cas12a–edited stem cell therapy, resulted in elimination of vaso-occlusive crises in 27 of 28 patients over a median 9.5 months of follow-up in this phase 1–2 trial (N=28). By 6 months, mean total hemoglobin rose from 9.8 at baseline to 13.8 g/dL, and fetal hemoglobin increased from 2.5% to 48.1%, with durable effects. Adverse events were consistent with busulfan-based myeloablative conditioning and autologous stem cell transplant.
The trial was halted early when the sponsor suspended clinical development after not being able to find a commercial partner. Each of the two existing FDA-approved gene therapy sickle cell treatments cost roughly $2 to $3 million for the one-time treatment; including hospital costs, these largely curative treatments can cost upward of $4 million.
Cost and logistics remain prohibitive, keeping the number of treated U.S. patients under about 100, despite a potential treatment population in the U.S. of around 20,000. Unlike bone marrow transplant, another option with similar outcomes, gene-editing therapies use a patient’s own cells, thereby avoiding donor matching, graft rejection, and graft-versus-host disease.
“We have seen that a benefit of this CRISPR/Cas12a gene-editing technology is that there is no rejection, so it's different from traditional bone marrow transplants, which is standard treatment for sickle cell patients currently,” said lead author Dr. Rabi Hanna, Chair of the Pediatric Hematology-Oncology & Blood and Bone Marrow Transplant Division of Cleveland Clinic Children’s. “Our aim has been to achieve a functional cure to help prevent any future damage caused by sickle cell disease, and these latest results are compelling.”
Source: Hanna R, et al. N Engl J Med. April 1, 2026. CRISPR-Cas12a Gene Editing of HBG1 and HBG2 Promoters to Treat Sickle Cell Disease