Clinical Outcomes of CRISPR-Cas9 Mediated Gene Editing in Patients with Sickle Cell Disease: A Biotechnology-Based Therapeutic Approach

Introduction: Sickle cell disease (SCD) is a severe monogenic disorder with limited curative options beyond allogeneic stem cell transplantation. Objective: To evaluate the clinical efficacy and safety of CRISPR-Cas9 mediated gene editing in patients with SCD undergoing autologous hematopoietic stem cell transplantation. Methodology: This prospective, single-arm, open-label interventional clinical trial was conducted at the Department of Hematology and Clinical Biotechnology, The University of Lahore, in collaboration with the National Institute for Genomics & Advanced Biotechnology (NIGAB), a division of the National Agricultural Research Centre (NARC), Islamabad, from April 2022 to March 2024. A total of 42 patients aged 12–40 years with homozygous SCD underwent autologous transplantation following CRISPR-Cas9 mediated editing of either the HBB gene or BCL11A erythroid enhancer. Clinical, hematologic, molecular, and immunologic outcomes were assessed at baseline, 12 months, and 24 months. Data analysis included paired t-tests and repeated measures ANOVA. Results: The mean editing efficiency was 62.35% ± 9.42%. Hemoglobin levels improved from 7.42 ± 1.12 g/dL at baseline to 11.23 ± 1.07 g/dL at 24 months (p < 0.001), and reticulocyte counts decreased from 10.18 ± 2.45% to 3.94 ± 1.19% (p < 0.001). At 24 months, 92.31% achieved transfusion independence, 84.62% had a ≥90% reduction in vaso-occlusive crises, and 76.92% entered clinical remission. HbF levels >20% were maintained in 87.18% of patients, and sustained gene expression was observed in 94.87%. Multilineage hematopoietic reconstitution was confirmed via flow cytometry. No serious adverse events or deaths occurred during follow-up. Conclusion: CRISPR-Cas9 gene editing shows high efficacy, safety, and potential as a transformative therapy for SCD.