PURPOSE: Sickle Cell Disease (SCD) is a monogenic, autosomal recessive disorder caused by mutations in the β-globin gene, resulting in the production of abnormal hemoglobin S (HbS). When deoxygenated HbS polymerizes, it causes red blood cells to become sickle-shaped, and prone to hemolysis. These abnormal and sickled cells obstruct small blood vessels, leading to vaso-occlusion and tissue ischemia, contributing to multiple complications. SCD impacts nearly 8 million people worldwide, and is estimated to affect 500,000 newborns annually. Historically, potentially curative therapies have been limited, but advances in fetal diagnosis and gene-editing technologies have highlighted the potential use of in utero gene therapy as a strategy to correct the β-globin mutation before clinical disease onset. This scoping review summarizes the current evidence on in utero and fetal gene-editing strategies for SCD.
METHODS: A systematic search of PubMed, Embase, and Scopus was conducted from database inception through September 2025 following PRISMA-ScR guidelines. Eligible studies included preclinical and translational investigations, early clinical reports, and expert policy or consensus statements focusing on in utero gene therapy or fetal gene editing for SCD. 25 studies met inclusion criteria and were categorized into 4 domains: ex vivo or in vivo gene editing, in utero gene editing, transplantation and tolerance, and reviews/policy/framework.
FINDINGS: Preclinical studies demonstrated that targeted in utero gene editing can achieve postnatal correction of disease-relevant alleles in animal models using CRISPR-Cas9 and base-editing technologies. Lipid nanoparticle (LNP) and viral vector delivery platforms enabled efficient editing of fetal hematopoietic stem cells, supporting long-term persistence of edited genes. Transplantation studies showed that fetal immune tolerance can persist as well. Review and consensus statements emphasized ethical, regulatory, and procedural considerations, including maternal autonomy, risk assessment, and long-term monitoring. Collectively, the evidence supports the feasibility of prenatal intervention as an acceptable and potentially curative approach for SCD.
IMPLICATIONS: In utero gene therapy represents a promising strategy for early correction of the β-globin mutation, with the potential to prevent disease onset and reduce long-term morbidity. However, translation to clinical practice will require additional studies and nuanced ethical oversight. Future research should prioritize the optimal timing of intervention, maternal-fetal immune compatibility, and equitable access to ensure accessible clinical implementation.
