Efficacy, Safety, and Treatment-Delivery Feasibility of Autologous Gene Therapy for Sickle Cell Disease: A Systematic Review With Descriptive Synthesis of Clinical Trials.

Abstract

Severe sickle cell disease (SCD) leads to recurrent vaso-occlusive events (VOEs), progressive organ damage, and premature death. Autologous gene therapy has emerged as a potential curative strategy, but trial efficacy must be interpreted together with mobilization, apheresis collection, manufacturing, conditioning, cost, fertility preservation, and long-term surveillance requirements. To evaluate the efficacy, safety, and treatment-delivery feasibility of autologous gene therapy for SCD across lentiviral, shmiR-BCL11A, CRISPR-Cas9, CRISPR-Cas12a, and base-editing platforms. We searched PubMed, Embase, Scopus, Cochrane CENTRAL, ClinicalTrials.gov, FDA, and EMA sources, and ASH/EHA/EBMT/ASPHO conference proceedings through June 23, 2026. Eligible studies were interventional trials or long-term follow-up studies of autologous gene therapy for SCD. Two reviewers independently screened records, extracted data, and assessed risk of bias. Because endpoint definitions were heterogeneous and fewer than three prospectively comparable cohorts were available for the main efficacy outcomes, formal pooling and forest plots were not performed; outcome proportions are presented descriptively. The updated synthesis included 25 reports describing nine interventional clinical programs and associated follow-up reports, with 148 infused patients across lentiviral, shmiR, CRISPR-Cas9, CRISPR-Cas12a, and base-editing platforms. Prospectively defined VF12 was 96.7% (29/30) in the exa-cel pivotal cohort, and severe VOE resolution was 100% (25/25) in the lovo-cel pivotal cohort; both products achieved transfusion independence in evaluable patients. Reni-cel and risto-cel added contemporary Cas12a and base-editing evidence, with early follow-up showing high HbF induction and few or no reported post-infusion VOEs, but follow-up was shorter, and endpoints were not pooled with pivotal VF12 cohorts. Treatment-delivery outcomes differed across programs, including 44/46 infused for exa-cel and 35/47 infused for lovo-cel. Autologous gene therapy for SCD produces substantial short- to medium-term reductions in severe VOEs and improves hemoglobin biology, but certainty remains limited by single-arm designs, small samples, evolving protocols, and incomplete long-term follow-up. Successful delivery depends on separable processes: transfusion preparation, mobilization, apheresis collection, ex vivo manufacturing/editing, product release, conditioning, and reinfusion. Long-term safety, fertility, organ outcomes, reimbursement, and global scalability remain unresolved implementation barriers.