The Impact of Brain-Derived Neurotrophic Factor rs6265 (Val66Met) Polymorphism on Therapeutic Electrical Stimulation for Peripheral Nerve Regeneration: A Preclinical Study of Therapy-Genotype Interactions

INTRODUCTION/AIMS: Therapeutic electrical stimulation (TES) shows promise in enhancing nerve regeneration, but outcomes vary widely. This study investigates the impact of the rs6265 single nucleotide polymorphism (SNP) on TES efficacy in a preclinical rat model and human stem cell-derived motor neurons. METHODS: Wild-type (WT) and rs6265 variant rats underwent sciatic nerve transection and received either TES or sham treatment. Muscle reinnervation was assessed through compound muscle action potentials and muscle fiber cross-sectional area. Isogenic human iPSC-derived motor neurons were used to study activity-dependent brain-derived neurotrophic factor (BDNF) secretion. RESULTS: WT rats that received TES (WT Estim) showed improved muscle cross-sectional area, electrophysiological muscle reinnervation, muscle fiber size, and NMJ reinnervation compared to Sham [p = 0.0468, p < 0.0001, p = 0.0160, p < 0.0001, respectively]. In contrast, rs6265 allele carriers did not experience a benefit of TES (rs6265 Estim) when compared to the Sham treatment [p = 0.9754, p = 0.8606, p = 0.9815, p = 0.1047, respectively]. Additionally, rs6265 allele carriers exhibited impaired activity-dependent BDNF secretion in vitro. DISCUSSION: The rs6265 polymorphism influences TES efficacy, highlighting the need for personalized approaches in peripheral nerve injury (PNI) treatment. These findings suggest that genetic screening could optimize therapeutic outcomes. Understanding genetic factors affecting TES response can enhance treatment strategies for PNI, potentially improving patient recovery and reducing outcome variability.