Precision Gene Therapy for Monogenic Neurological Disorders: Emerging Technologies, Safety, and Mechanism–Modality Matching

Monogenic neurological disorders remain challenging to treat because of the restricted permeability of the blood–brain barrier (BBB), the limited regenerative capacity of the central nervous system (CNS), and the difficulty of achieving therapeutically meaningful correction in disease-relevant cell populations. Rapid advances in gene-based therapies are expanding the range of genetic defects that may be amenable to therapeutic intervention, shifting the field from symptomatic management toward mechanism-based intervention. In this Review, we examine emerging gene- and RNA-based therapeutic strategies across representative disorders, including spinal muscular atrophy (SMN1/SMN2), SOD1-associated amyotrophic lateral sclerosis, and SCN1A-related Dravet syndrome, with particular emphasis on vector engineering, RNA modulation, genome editing, and large-cargo delivery approaches. We further discuss patient-derived organoids and organ-on-a-chip systems as human-relevant platforms for preclinical validation, as well as emerging therapeutic contexts such as in utero intervention. Rather than treating these technologies as interchangeable, we propose a mechanism–modality matching framework in which therapeutic selection is guided by disease mechanism, cargo requirements, target-cell distribution, durability, reversibility, immune risk, and therapeutic timing. Particular attention is given to modality-specific safety, including AAV-associated hepatotoxicity and immunogenicity, as well as unintended genomic alterations and long-term genome integrity associated with genome editing. Precision gene therapy should therefore be defined not by the use of the most advanced technology, but by selection of an intervention that achieves sufficient molecular correction with an appropriate balance of efficacy, durability, reversibility, delivery feasibility, and long-term safety.