Valosin-containing protein (VCP) disease is an autosomal dominant disease caused by gain-of function pathogenic variants in the VCP gene. The disease is associated with inclusion body myopathy, with early-onset Paget’s disease of the bones, frontotemporal dementia and familial amyotrophic lateral sclerosis, also known as multisystem proteinopathy 1 (MSP1). We hypothesize that regulating VCP hyperactivity to normal levels can reduce the disease pathology. We propose this could be achieved through the reduction of expression in VCP with the use of antisense oligonucleotides (ASOs). _x000D_
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In this study, we utilized the transgenic humanized mouse model of VCP disease which overexpresses the humanized VCP gene with the severe A232E mutation. After establishing the validity of the mouse model, we screened ASOs specifically targeting the human VCP gene in the mice harboring wildtype VCP transgene weekly for 8 weeks. ASO2 was selected for its good safety profile in mice. Thereafter, we treated the VCP A232E mice with ASO2 starting from 6 months of age for a 3 month duration and performed monthly motor tests. We then developed patient derived (R155H) iPSC derived skeletal muscle progenitor cells (SMPCs) and assessed the effect of ASO2 in this model._x000D_
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ASO2 showed over 50% knockdown of VCP at the mRNA level and a similar knockdown effect at the protein level. Interestingly, ASO2 treatment in VCP A232E mice showed significant improvements in the inverted screen compared to mice treated with control ASO. We also found significant reduction in VCP at the protein level on treatment with ASO2 as compared to control ASO. ASO2 was well tolerated up to 1200 nM concentration and significantly reduced mRNA and protein expression in SMPCs cells. These results suggest that knockdown of the mutant VCP allele early in asymptomatic mice and in SMPCs could be beneficial in preventing progression of the myopathy, and holds promise for treatment of clinical features in MSP1 patients.