2026 Volume 37 Issue 1 Pages 6-12
Peripheral nerve injury is primarily managed by surgical repair, yet functional outcomes remain limited in long-gap defects, delayed repair, and chronic denervation. Gene therapy provides a complementary framework because it can act on three anatomical layers: neuronal cell bodies (dorsal root ganglia and motor neurons) , the injured nerve segment (including Schwann cells and biomaterial conduits) , and denervated target muscles. Across these compartments, adeno-associated virus (AAV) , lentivirus, and non-viral platforms enable delivery of neurotrophic factors, transcriptional regulators, and modulators of inflammation, angiogenesis, myelination, and neuromuscular junction stability. A central challenge is dosing in space and time. Potent chemoattractants such as glial cell line-derived neurotrophic factor (GDNF) can enhance axonal entry into grafts or conduits, but sustained high local expression may trap regenerating axons and promote misrouting (the “candy-store effect”) . Accordingly, clinically plausible strategies increasingly combine local confinement with tunable expression systems (e.g., drug-inducible switches) , cell-type–biased promoters, staged interventions matched to Wallerian degeneration and remyelination, and objective potency assays. A major recent advance is direct reprogramming of fibroblasts into Schwann-like cells by forced expression of SOX10 and KROX20 (EGR2) , generating functional induced Schwann cells capable of supporting axons and forming myelin. Because this approach bypasses pluripotent intermediates, it can shorten manufacturing lead time and may reduce tumorigenic concerns while preserving scalability. We discuss how induced cells can serve as a source of “designer” Schwann cells for transplantation and, potentially, as living gene-delivery vehicles equipped with regulated secretion and safety switches. This review summarizes key developments over the past two decades in peripheral nerve gene therapy, emphasizing delivery routes, regulatory control of transgene expression, and a translational roadmap integrating vector design, chemistry, manufacturing, and controls (CMC) considerations, preclinical safety testing, and surgical workflows to achieve clinically meaningful functional recovery. We also highlight synergy with perioperative electrical stimulation and rehabilitation-based timing optimization.
