Translating CRISPR to Practice in the Clinic: Transformative Therapy in Hemoglobinopathies and Emerging Applications in Malignancies.

Abstract

Exagamglogene autotemcel, the first clustered regularly interspaced short palindromic repeats (CRISPR)-based gene-editing therapy to enter clinical practice, has established genome editing as a curative-intent option for eligible patients with severe sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT). Ex vivo CRISPR-Cas9 editing of autologous CD34-positive hematopoietic stem and progenitor cells to reactivate fetal hemoglobin has produced durable freedom from severe vaso-occlusive crises in SCD and sustained transfusion independence in TDT. This approach offers a donor-independent alternative to allogeneic hematopoietic stem-cell transplantation without graft rejection or graft-versus-host disease. Hemoglobinopathies, therefore, provide the first clinically validated delivery model for CRISPR therapeutics. Successful implementation, however, requires more than editing efficacy. It depends on structured referral, candidacy assessment, organ function review, mobilization and collection, centralized manufacturing, pharmacokinetic-guided myeloablative conditioning, transplant-level supportive care, fertility preservation, psychosocial support, and prolonged surveillance coordinated among primary hematologists and cellular therapy programs. Key barriers include stem cell collection, conditioning-related toxicity, cost, reimbursement friction, and persistent inequities in access. Long-term follow-up and registry participation are necessary to evaluate outcomes beyond pain crises, identify late toxic effects, and compare real-world effectiveness across gene editing, gene addition, and allogeneic transplantation. In oncology, CRISPR-based therapy remains investigational, with early clinical feasibility demonstrated in relapsed or refractory B-cell malignancies, T-cell malignancies, AML, multiple myeloma, and selected solid tumors. For hematologists, oncologists, and transplant and cellular therapy programs, the central challenge is to integrate CRISPR into practice with the rigor required for any high-risk curative therapy: careful patient selection, disciplined delivery, and long-term accountability.