In Utero Gene Therapy for Sickle Cell Disease: Current Evidence, Ethical Considerations, and Future Directions-A...

Area of Science:

• Genetics and Genomics
• Hematology
• Regenerative Medicine

Background:

• Sickle Cell Disease (SCD) is a severe monogenic disorder affecting millions globally, characterized by abnormal hemoglobin S (HbS) leading to red blood cell sickling, vaso-occlusion, and tissue damage.
• Current treatments for SCD are limited, with few curative options available, highlighting the need for innovative therapeutic strategies.
• Advances in gene editing and fetal diagnosis present an opportunity for prenatal intervention to correct the underlying genetic defect before disease manifestation.

Purpose of the Study:

• To review the current evidence on in utero gene therapy and fetal gene editing for Sickle Cell Disease.
• To assess the feasibility and potential of prenatal correction of the β-globin mutation for SCD.

Main Methods:

• A systematic literature search was performed across PubMed, Embase, and Scopus databases, adhering to PRISMA-ScR guidelines.
• Included studies encompassed preclinical, translational, and early clinical investigations, alongside policy and consensus statements on in utero gene editing for SCD.
• Twenty-five studies were selected and categorized into gene editing techniques, transplantation, and ethical/regulatory frameworks.

Main Results:

• Preclinical studies using CRISPR-Cas9 and base editing demonstrated successful postnatal correction of SCD-related mutations in animal models.
• Lipid nanoparticle and viral vector delivery systems effectively edited fetal hematopoietic stem cells, ensuring long-term gene persistence and leveraging fetal immune tolerance.
• Ethical and regulatory discussions emphasized maternal autonomy, risk assessment, and long-term monitoring, supporting prenatal intervention as a viable curative strategy.

Conclusions:

• In utero gene therapy offers a promising avenue for early correction of the β-globin mutation, potentially preventing SCD onset and mitigating long-term health issues.
• Clinical translation requires further research into optimal intervention timing, maternal-fetal immune compatibility, and ethical considerations.
• Ensuring equitable access to these advanced therapies is crucial for widespread clinical implementation and addressing the global burden of SCD.