CRISPR-Based Mediated Reactivation of Fetal Hemoglobin as a Therapeutic Strategy for Hemoglobinopathies: Evidence from Preclinical to Clinical Trials in Sickle Cell Disease and β-Thalassemia

β-Hemoglobinopathies, including sickle cell disease (SCD) and β-thalassemia, are inherited disorders caused by mutations in the β-globin gene (HBB), leading to defective production of adult hemoglobin (HbA), vaso-occlusive crises, and rapid destruction of erythrocytes as they leave the bone marrow, resulting in hemolytic anemia. In recent years, CRISPR-based genome-editing technologies have emerged as promising therapeutic strategies to reactivate fetal hemoglobin (HbF) expression by targeting key regulatory elements, including the BCL11A enhancer and the HBG1/HBG2 promoters. This review aimed to synthesize available scientific evidence from PubMed, Scopus, Web of Science, and ClinicalTrials.gov on preclinical and clinical studies evaluating CRISPR-based genome-editing approaches for the treatment of SCD and β-thalassemia. This review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) Statement. A total of 247 records were identified; 20 studies met the inclusion criteria and were included in the qualitative synthesis. The included studies investigated various CRISPR-based platforms, including nuclease-mediated editing and base-editing strategies, to reactivate HbF expression. The studies reported durable increases in HbF levels, with therapeutic effects persisting for up to 22 months after treatment. Clinically, these outcomes were associated with the elimination or marked reduction of vaso-occlusive crises in patients with SCD and with transfusion independence in patients with β-thalassemia. Overall, the available evidence suggests that CRISPR-based HbF reactivation is a promising therapeutic approach for β-hemoglobinopathies, although long-term efficacy and safety data remain necessary.