Paving a way to treat spastic paraplegia 50

Abstract

Spastic paraplegia 50 (SPG50) is a rare neurodegenerative disease caused by loss-of-function mutations in AP4M1. 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 the JCI, Chen et al. provide promising data from preclinical studies that evaluated the efficacy and safety profiles of an AAV-mediated AP4M1 gene replacement therapy for SPG50. AAV/AP4M1 gene 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/AP4M1 gene therapy to clinical trials.

Figure 1. AAV/AP4M1 gene therapy rescues AP4M1-deficient phenotypes.

(A) AP-4 is composed of four subunits, including AP4B1, AP4E1, AP4M1, and AP4S1. The AP4M1 subunit recognizes and binds to specific cargo proteins, such as ATG9A, and facilitates vesicle budding from the trans-Golgi Network (TGN) to peripheral compartments.(B) Loss of AP4M1 prevents the formation of functional AP-4, leading to the retention of its cargo proteins on TGN, resulting in dysfunction and degeneration of neurons. (C) Chen et al. (9) show that AAV/AP4M1 gene therapy can partly rescue functional defects in the SPG50 cellular and Ap4m1-KO animal models.