Gene Therapy Approaches for Rare Genetic Diseases: Current Advances, Challenges and Future Perspectives

Abstract

Rare genetic diseases are a highly heterogeneous group of disorders affecting a small number of patients but collectively pose a significant global health burden. Current treatments offer clinical benefits but often fail to correct molecular defects, reach tissues, avoid immunity, or eliminate repeated dosing. These limitations are especially pronounced in cases of molecularly heterogeneous rare diseases affecting small patient populations with anatomically inaccessible tissues. Gene therapy helps to address such limitations by targeting the causal gene or transcript. In this chapter, we examine the molecular basis of rare genetic diseases, major delivery platforms, genome editing technologies, and representative clinical applications. The adeno-associated virus and lentiviral vector systems are important viral vectors, as they have higher transduction efficiency, while lipid nanoparticles, polymer-based carriers, and physical methods provide scalable and possibly engraftable strategies. Gene addition, disruption, and precise sequence correction can be accomplished using CRISPR–Cas nucleases, base editors, and prime editors, but the challenges of delivery, immunogenicity, off-target activity, and manufacturing are significant. Diseases and disorders such as spinal muscular atrophy, Duchenne muscular dystrophy, and hemophilia B are examples of how disease mechanism, target tissue, durability, and safety impact therapeutic designs and clinical translation strategies. The future of gene therapy for rare diseases depends on the widespread adoption of patient-specific designs, expedited approval pathways with regulatory agencies, and standardized manufacturing processes. Expanding newborn screening for early diagnosis, capid and promoter engineering with high tissue specificity, improving immunosuppression protocols, and establishing long-term follow-up registries are of critical importance.