CRISPR-Edited Cell Therapy Exa-cel Eliminates Pain Crises in 97% of Sickle Cell Patients

Sickle cell disease is a genetic disorder in which abnormal hemoglobin turns red blood cells into a sickle shape, blocking blood vessels and causing severe pain crises. Dr. Haydar Frangoul of the Sarah Cannon Research Institute in the United States and colleagues reported in NEJM the phase 3 results of exagamglogene autotemcel (exa-cel), a CRISPR-Cas9 gene-editing cell therapy. The patient's own CD34+ hematopoietic stem cells are taken out and the erythroid-specific enhancer of the BCL11A gene is edited, which switches back on the production of fetal hemoglobin that is turned off as a person grows.

Single-Arm Open-Label Phase 3, 44 Treated

The participants were patients aged 12 to 35 who had had at least 2 severe vaso-occlusive crises per year in the previous 2 years. Before the edited cells were infused, they received conditioning with busulfan to clear out the bone marrow. The primary endpoint was the proportion of patients with no severe vaso-occlusive crisis for at least 12 consecutive months. Forty-four patients were treated (median follow-up 19.3 months), and neutrophils and platelets engrafted in all of them. Of 30 evaluable patients, 29 (97%) met the primary endpoint, and all 30 had no hospitalizations for these crises.

The safety profile was in the range expected from myeloablative busulfan conditioning and autologous hematopoietic stem cell transplantation, and no cancers occurred.

Significance and Limits

The result shows that gene editing alone, without a viral vector, can suppress disease symptoms over the long term. However, this is a single-arm study without a control group and with a small sample, and the burden of high-dose chemotherapy conditioning, the high cost, and long-term safety over decades remain open issues. The developers, Vertex and CRISPR Therapeutics, took part in the study.