Muscle-targeted Klotho Gene Therapy Ameliorates ALS Hallmarks by Addressing Multiple Disease Mechanisms in SOD1G93A Mice

Abstract The antiaging protein a-Klotho (KL) exhibits neuroprotective and myoregenerative properties, mitigating age-related neurodegeneration and promoting muscle regeneration. This study harnesses its pleiotropic properties in the context of Amyotrophic Lateral Sclerosis (ALS), a motoneuron disease lacking effective treatments due to its diverse pathophysiological mechanisms. By overexpressing secreted KL in skeletal muscles of SOD1G93A mice with myotropic viral vectors we aimed to directly protect muscles and exert a paracrine effect on motoneuron (MN) terminals. Secreted KL preserved MNs and neuromuscular junctions, and mitigated glial reactivity, resulting in maintained muscle mass, improved neuromuscular function, delayed disease onset, and extended survival. Even when administered during symptomatic stages, KL slowed down ALS progression. Transcriptomic and proteomic studies in muscles revealed significant correction of pathophysiological mechanisms involved in ALS disease, unveiling novel roles for KL. These findings highlight the potential application of muscle-secreted KL in ALS regardless of its origin and suggest broader therapeutic implications.