Correction of VCP Disease Pathology with Antisense Oligonucleotides

/ABSTRACT Valosin -containing protein (VCP) multisystem proteinopathy 1 or MSP1 is an autosomal dominant disorder associated with inclusion body myopathy, Paget's disease of the bone, frontotemporal dementia and amyotrophic lateral sclerosis (ALS). It is caused by missense mutations of the valosin containing gene, and in vitro assays of VCP mutants have shown enhanced ATPase activity, suggesting a gain of function mechanism. VCP shares common pathologies including disrupted autophagy and TDP-43 mislocalization with more common neuromuscular diseases. Using antisense oligonucleotides (ASOs) for the treatment of neuromuscular diseases is a burgeoning field with promising research. Currently there are clinical trials involving ASOs for various neuromuscular diseases with gain of function mutations in genes such as SOD1, and FUS. Major gaps: There is currently no treatment for the neuromuscular component of VCP disease which results in severe muscle weakness, and early death. The Kimonis lab has taken the lead in mechanistic and translational research in VCP disease. The rationale for this study is to decrease VCP activity using ASOs to a level commensurate with the gain of function to ameliorate disease pathology. Our ultimate goal is to develop a therapy to improve the progressive myopathy in VCP disease. Preliminary results: ASO technology has emerged as a powerful direct treatment of genetic disorders such as spinal muscular atrophy, Duchenne muscular dystrophy, and ALS. ASOs targeting VCP was designed by Ionis Pharmaceuticals Inc. and preliminary studies in the patient iPSCs derived myoblasts and humanized overexpressed VCP A232E mouse showed that ASO2 had the best safety and improvement in TDP-43 levels, the hallmark of VCP pathology. Treatment with ASO2 reduced VCP mRNA expression by ~ 48% and protein expression by ~ 40% in myoblasts generated by differentiating patient derived iPSCs. On treating the VCP A232E overexpressed mouse with ASO2, VCP mRNA level in the muscle reduced by 50% and the protein level reduced by 38%, additionally the TDP-43 and autophagy pathological markers in tissue improved. Hypothesis: We propose that early treatment with the optimum dose of ASOs in the patient iPSCs derived myoblasts and motor neurons and humanized VCPA232E mice will correct VCP pathology. Thus, we propose these two specific aims: Aim 1: Correction of the TDP and autophagy pathology using VCP ASOs in patient iPSCs derived myoblasts and motor neuron cells. Aim 2. Correction of muscle pathology and weakness in the humanized VCPA232E mice using ASOs. Success in this study will provide a novel effective treatment for VCP and other dominant diseases Robust preclinical data in patient derived myoblasts and the VCP knock-in mouse model will thus pave the way for regulatory approval for a patient trial of ASOs. Successful therapeutics in VCP disease also has huge translational potential for more common diseases with which it also shares common pathologies including disrupted autophagy and TDP-43 pathology. Project Number: 1R21AG093390-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: VIRGINIA KIMONIS | Institution: UNIVERSITY OF CALIFORNIA-IRVINE, IRVINE, CA | Award Amount: $431,750 | Activity Code: R21 | Study Section: Skeletal Muscle and Exercise Physiology Study Section[SMEP] View on NIH RePORTER: https://reporter.nih.gov/project-details/11120803