EFFICACY AND SAFETY OF GENE THERAPY IN β-HEMOGLOBINOPATHIES: A SINGLE-ARM META-ANALYSIS

Abstract

Objective: Sickle cell disease (SCD) and β-thalassemia (BT) are genetic disorders caused by variants of the HBB gene, which encodes β-globin. However, the current standard of treatment for these disorders has a fair prognosis. Consequently, a novel clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9 therapy was developed, seeking to undermine the β-globin defects by reactivating fetal hemoglobin production through editing of the erythroid enhancer region of BCL11A. This therapy offers a promising alternative for treating those β-hemoglobinopathies. Therefore, we conducted a systematic review aiming to consolidate and summarize current knowledge on the efficacy and safety of this new treatment specifically in BT or SCD. Methods: We performed a systematic literature review and a meta-analysis adhering to PRISMA guidelines. Our search strategy encompassed PubMed, Embase, and Cochrane Library databases, utilizing the key terms ’CRISPR-Cas9’, ’BCL11A’ and ’b-hemoglobinopathies’. Efficacy outcomes included total hemoglobin, free vaso-occlusive events at 12 months, transfusion independence and percentage of F cells (percentage of red cells expressing fetal hemoglobin). Safety outcomes comprised most common adverse events (AEs), and grade 3 or higher AEs. Data were summarized using pooled mean for continuous outcomes and pooled proportion for dichotomous outcomes, with 95% confidence intervals. I²was used to assess heterogeneity. Statistical analyses were performed using R Studio 4.4.1. Results: Out of 1388 initially identified studies, 55 were included in the final analysis, with 110 patients with β-hemoglobinopathies, of which 59.09% had transfusion-dependent BT and 40.91% had SCD. The total hemoglobin was 12.71 (95% CI 12.32; 13.10). In SCD patients, the rate of free vaso-occlusive events at 12 months was 90.46% (n = 32, 95% CI 29.66, 100.00). In Transfusion-Dependent BT patients, the rate of transfusion independence was 99.38% (n = 49, 95% CI 90.95, 100.00). The F cells range was 93% to 99.7% in 6 months. Regarding AEs, febrile neutropenia occurred in 46.36% of patients (47.73% in TDBT and 43.48% in SCD), stomatitis occurred in 45.45% of patients (54.55% in SCD and 37.68% in TDBT), and thrombocytopenia occurred in 36.36% of patients (25.00% in SCD and 42.03% in TDBT). Overall, 86.36% of patients experienced AEs of grade 3 or higher. Discussion: The efficacy results from across all studies analyzed show unprecedented success in changing the natural course of both diseases during the follow up time frame. However, it is safe to say that there is a myriad of challenges regarding real world application of gene therapy, such as the millionaire cost for each patient and the considerable treatment morbidity shown in the safety data results, which would confine these patient's care to major reference hospitals in the country. Therefore, gene therapy stays as a possible, promising, but distant treatment for thalassemia and sickle cell disease in Brazil. Conclusion: The data suggest that CRISPR-Cas9 therapy targeting BCL11A presents a promising outlook for the treatment of patients with β-hemoglobinopathies. However, the therapy has significant AEs, particularly grade 3 or higher. Nevertheless, additional studies with larger samples and long-term follow-up will be necessary to confirm these initial results.