Pathogenic variants in Valosin Containing Protein (VCP) gene lead to an autosomal dominant multisystem proteinopathy (MSP1), characterized by inclusion body myopathy, Paget disease of bone and frontotemporal dementia, and amyotropic lateral sclerosis. The disease mechanism is driven by a gain-of-function effect of the VCP missense variants. A knock-in VCP mouse model carrying the common R155H mutation exhibits several features of the human disease, with homozygous VCP R155H/R155H mice showing progressive weakness and severe pathology leading to premature dead before 3 weeks of age.
Homozygous VCPR155H/R155H mice on a normal chow diet do not survive past weaning age. However, survival rates improve significantly with a lipid-enriched diet, allowing over 50% of the pups to reach young adulthood. Additionally, delayed weaning and removal of healthy littermates further enhance survival, extending lifespan from approximately three weeks to over twenty weeks.
Using this mouse model, we confirmed the myotropic AAV9 variant, AAVMYO has favorable attributes including more specific muscle tropism across all muscles tested, effective virus dosage, weak viral immune response, and no toxicity in VcpR155H/+ mice. We next investigated muscle-targeted gene therapy using the AAVMYO vector to deliver therapeutic payloads to muscle tissue locally via intramuscular injection or systematically via retro-orbital injection. Treatment with AAVMYO carrying microRNA targeting mutant VCP, with or without wild-type VCP replacement, resulted in improvement in muscle pathology, TDP-43 and autophagy markers in VCPR155H/R155H mice.
Conclusion: Our approach, combining a high-fat diet with strategic weaning practices, provides a useful disease model for studying MSP1. Downregulation of the mutant VCP allele via AAVMYOP-microRNA VCP demonstrates promising therapeutic effects on muscle pathology in in VCPR155H/R155H mice. These preclinical findings provide proof of principle validation for AAV-based gene therapy to deliver therapeutic benefits for patients with VCP-related diseases and similar multisystem proteinopathies.