CRISPR Gene-Editing Therapies for Sickle Cell Disease and Beta- Thalassemia: Clinical Outcomes, Risks and Safety Profiles. A Systematic Review

الملخص

Background: Sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) are severe inherited hemoglobinopathies associated with chronic anemia, organ damage, and reduced life expectancy. Conventional management strategies such as lifelong transfusions and iron chelation therapy improve survival but fail to correct the underlying genetic defect. Hematopoietic stem cell transplantation remains the only curative option but is limited by donor availability and transplant-related risks.

Methods: This systematic review synthesized evidence from 2016–2025, including mechanistic studies and clinical trials of CRISPR/Cas9-based therapies. Literature was retrieved from PubMed, MEDLINE, Embase, Scopus, Web of Science, Google Scholar, and ClinicalTrials.gov, following PRISMA guidelines. Studies targeting BCL11A enhancer disruption and fetal hemoglobin (HbF) reactivation were prioritized.

Results: Preclinical studies demonstrated that CRISPR-mediated disruption of BCL11A effectively derepresses γ-globin expression, providing a strong biological rationale for HbF induction. Clinical trials of exagamglogene autotemcel (exa-cel) showed sustained HbF elevation, elimination of vaso-occlusive crises in SCD, and durable transfusion independence in TDT. Pediatric cohorts achieved comparable outcomes, confirming feasibility across age groups. Reported adverse events were primarily linked to conditioning regimens rather than gene-editing itself, with no confirmed off-target genomic instability.

Conclusion: CRISPR/Cas9-based therapies represent a paradigm shift in genomic medicine, offering functional cures for β-hemoglobinopathies. While long-term monitoring, cost, and accessibility remain challenges, current evidence highlights durable efficacy and acceptable safety profiles. These findings underscore the transformative potential of CRISPR gene editing in redefining treatment standards for inherited blood disorders.