Spastic paraplegia 50 (SPG50) is a rare neurodegenerative disease caused by loss-of-function mutations inAP4M1. There are no effective treatments for SPG50 or any other type of SPG, and current treatments are limited to symptomatic management. In this issue of theJCI, Chen et al. provide promising data from preclinical studies that evaluated the efficacy and safety profiles of an AAV-mediatedAP4M1gene replacement therapy for SPG50. AAV/AP4M1gene replacement partly rescued functional defects in SPG50 cellular and mouse models, with acceptable safety profiles in rodents and monkeys. This work represents a substantial advancement in therapeutic development of SPG50 treatments, establishing the criteria for taking AAV9/AP4M1gene therapy to clinical trials.