CRISPR Cas-9 Editing for Treating Sickle Cell Disease: A Systematic Review and Meta-Analysis

Introduction

Exagamglogene autotemcel (exa-cel) represents a novel nonviral cell therapy aimed at reactivating fetal hemoglobin synthesis through the ex vivo application of clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing. This process targets autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) at the erythroid-specific enhancer region of BCL11A. We performed a systematic review and meta-analysis of all clinical studies related to this therapy to evaluate its efficacy and safety in treating sickle cell disease (SCD).

Methods

A comprehensive search strategy was employed, incorporating keywords such as “CRISPR,” “exagamglogene autotemcel,” and “sickle cell disease.” The databases PubMed, Embase, and Medline were utilized to identify relevant studies. Inclusion criteria were based on clinical trials involving CRISPR/Cas9 gene editing for SCD treatment.

Results

A total of 34 patients were included in the analysis, comprising 26 males and 8 females with an average age of 25.51 years. The predominant genotype was βS/βS, observed in 30 patients. Key findings included an annualized rate of severe vaso-occlusive crises of 4.14, an average total hemoglobin level of 8.3 g/dL, and an average fetal hemoglobin level of 5.5 g/dL. The median number of mobilization cycles was 2. At 12 months, 32 out of 34 patients were free from vaso-occlusive crises, and 33 out of 34 were free from hospitalizations. The p-value for these outcomes was less than 0.0001, assuming a null hypothesis of a 50% response rate.

Discussion

Sickle cell disease (SCD) is a prevalent monogenic blood disorder characterized by severe pain, organ damage, and reduced life expectancy. Treatment options are notably limited, with hematopoietic stem cell transplantation from a matched related donor being the only curative approach. The ex vivo modification of autologous hematopoietic stem and progenitor cells, followed by transplantation of these genetically modified cells, offers a potential permanent cure applicable to all patients, regardless of donor availability or the risk of graft-vs-host disease. This review emphasizes the application of CRISPR/Cas9 gene editing in treating SCD, focusing on the correction of the β-globin (HBB) mutation and the induction of fetal hemoglobin to counteract cell sickling. We highlight significant accomplishments and challenges within this field, providing insights into the future potential of gene-editing therapies for curing SCD.

No relevant conflicts of interest to declare.