Advances and Challenges in Gene Therapy Methods for Central Nervous System Disorders: A Comprehensive Review

Abstract

Central nervous system (CNS) disorders of genetic origin remain largely incurable with conventional pharmacotherapy, which in most cases offers only symptomatic relief. Gene therapy aims instead at durable correction of the underlying molecular defect, but its application to the CNS is constrained by the post-mitotic nature of neurons, the architectural complexity of neural circuits, and the blood-brain barrier (BBB). This review summarises the current methodological landscape of CNS gene therapy, compares the available delivery paradigms and vector systems, and identifies the principal translational barriers that still limit clinical adoption. A narrative review of peer-reviewed original studies, clinical trial reports, regulatory approval documents and authoritative reviews published between 2009 and 2024 was performed. Sources were retrieved from PubMed, Scopus and Web of Science using combinations of the keywords listed below, and were organised according to a three-part analytical framework based on the route of vector delivery: ex vivo, in vivo and in situ. Lentiviral ex vivo modification of autologous haematopoietic stem cells has produced durable neurological stabilisation in X-linked adrenoleukodystrophy and metachromatic leukodystrophy through microglial repopulation and enzymatic cross-correction. Adeno-associated virus (AAV) vectors dominate in vivo delivery and underpin the two approved CNS-directed products, onasemnogene abeparvovec and eladocagene exuparvovec, whereas in situ delivery remains largely confined to neuro-oncology. Engineered capsids and non-viral carriers improve BBB traversal, while CRISPR-Cas9, base editing and prime editing extend the field from gene augmentation towards targeted genomic correction. Dose-dependent hepatotoxicity, complement activation, dorsal root ganglion toxicity, pre-existing anti-capsid immunity and insertional mutagenesis remain the dominant safety signals. CNS gene therapy has become a clinical reality for a small number of monogenic diseases. Its broader adoption depends less on the editing chemistry itself than on solving delivery, immunogenicity, long-term safety surveillance and cost-related equity problems.