In December 2023 the FDA Approved the First Therapy to Use CRISPR/Cas9 Gene Editing Technology in Humans. The Disease it Targets, Sickle Cell Disease, Has Been Treatable but Never Curable for the 100,000 Americans Living With It.

Sickle cell disease (SCD) is a hereditary blood disorder caused by a single point mutation in the beta-globin gene, producing abnormal hemoglobin that causes red blood cells to become rigid and sickle-shaped under deoxygenation. The downstream consequences are severe: chronic pain, anemia, organ damage, stroke, acute chest syndrome (ACS), and a profoundly shortened life expectancy. For decades, treatment has centered on managing symptoms and preventing complications rather than addressing the underlying genetic defect. Hematopoietic stem cell transplantation (HSCT) offered the only potential cure, but it was accessible to only 18% of SCD patients in the United States who had a matched sibling donor. The FDA approval of Casgevy in December 2023 changed that calculus. This narrative review from researchers across the United States, Pakistan, Nepal, and India examines what CRISPR/Cas9 gene therapy offers SCD patients, how it compares to existing treatments, and what open questions remain before it can be considered a broadly accessible cure.

Tariq et al. conducted a narrative review of published literature on CRISPR/Cas9 gene therapy for SCD, searching PubMed, Google Scholar, Embase, and Web of Science using Boolean operators covering sickle cell disease pathophysiology, traditional treatment approaches, and recent advances in gene therapy. Eligible studies were screened for relevance to the mechanisms, efficacy, and safety profiles of both traditional treatments and CRISPR/Cas9-based gene editing. The review evaluated Casgevy, formally known as exagamglogene autotemcel (exa-cel), against the existing therapeutic landscape including hydroxyurea, L-glutamine, voxelotor, crizanlizumab, blood transfusion, and allogeneic HSCT.

Casgevy works by harvesting a patient's own hematopoietic stem cells, editing them outside the body using CRISPR/Cas9 to disrupt the BCL11A gene, a repressor of fetal hemoglobin (HbF) production, and reinfusing the edited cells after myeloablative conditioning with busulfan chemotherapy. The result is a sustained increase in HbF expression, which inhibits the polymerization of sickle hemoglobin (HbS) and prevents red blood cells from sickling. In the CLIMB-SCD-121 trial that supported FDA approval, 96.7% of patients were free of vaso-occlusive crises (VOCs) for at least 12 consecutive months following treatment, and 100% were free of severe VOC-related hospitalizations for the same period (Frangoul et al., New England Journal of Medicine, 2024). Follow-up data from the same trial published in 2024 showed that the 29 patients reaching the primary endpoint remained free of VOCs at a median of 22.4 months.

In comparison, traditional treatments offer meaningful but incomplete benefit. Hydroxyurea, FDA-approved since 1998, increases HbF expression and reduces VOC frequency but requires lifelong administration, carries side effects including neutropenia and bone marrow suppression, and does not eliminate VOCs. L-glutamine, approved in 2017, reduces the intensity and frequency of painful episodes but similarly requires ongoing administration. Allogeneic HSCT remains the only other potentially curative option but is limited by donor availability, graft-versus-host disease risk, and transplant-related mortality. Casgevy sidesteps the donor availability constraint entirely by using the patient's own cells.

• —As a narrative review, this paper is subject to selection bias in the search strategy and relies on published literature, which may not capture all relevant studies. No formal quality assessment tool was applied to included studies.
• —The CLIMB-SCD-121 trial enrolled a carefully selected patient population. Long-term durability data beyond 22.4 months of follow-up is not yet available for the full cohort, and final data from the study was expected in the second half of 2025.
• —Off-target editing effects have not been detected to date, but longer follow-up is required to exclude them with confidence given the novelty of the technology.
• —The review does not fully address the practical barriers to access including treatment center availability, insurance coverage, and the biosafety and infrastructure requirements for administering this therapy at scale.

CRISPR/Cas9 gene therapy for sickle cell disease is one of the most consequential therapeutic advances in modern medicine. The efficacy data is striking and the mechanistic rationale is sound. The barriers that remain, cost, access, infrastructure, and long-term safety data, are not trivial, and they are not equally distributed. The technology works. Getting it to the patients who need it most is the harder problem, and it has not been solved.

Frangoul H, Altshuler D, Cappellini MD, et al. "Exagamglogene Autotemcel for Severe Sickle Cell Disease." New England Journal of Medicine. 2024;390(18):1649-1662. doi:10.1056/NEJMoa2309906. Note: full text requires subscription. Abstract available at: https://pubmed.ncbi.nlm.nih.gov/38657266/