Wildtype control, homozygous and heterozygous VCP R155H mice were gavaged daily with 15mg/kg CB-5083 or vehicle for five months. To evaluate the effect of CB-5083 on mouse motor function, weight, rotarod testing and grip strength were monitored monthly. To Furthermore, to assess the effect of CB-5083 on cellular pathology, immunoblotting and immunohistochemistry analysis were performed in muscle tissue to evaluate TDP43 and mitochondria pathology.

In parallel, IBMPFD patient-derived myoblasts were treated with variable dosage of CB-5083. Immunoblotting, and immunohistochemistry was performed to measure cellular pathology

Our studies showed that the IBMPFD mouse model tolerated CB-5083 treatment with improvement in motor behavior. Importantly, the pathological autophagy markers and TDP43 elevation in the IBMPFD mice were significantly reduced. Loss of muscle integrity and muscle pathology were also ameliorated. The improvements in pathology are associated with CB-5083’s modulation of VCP expression and autophagy pathways.

The VCP mouse model tolerated treatment with VCP inhibitor CB-5083 with improvement of motor behavior and cellular pathology. Additionally we saw improvement of the cellular pathology in patient-derived myoblasts. Our results suggest that CB-5083 is a potential safe and effective therapy in patients with VCP disease.