VCP/p97 inhibitor CB-5083 modulates muscle pathology in a mouse model of VCP inclusion body myopathy

VCP/p97 inhibitor CB-5083 modulates muscle pathology in a mouse model of VCP inclusion body myopathy

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Abstract Background Pathogenic gain of function variants in Valosin-containing metabo 15-gauge finish nailer cordless protein (VCP) cause a unique disease characterized by inclusion body myopathy with early-onset Paget disease of bone and frontotemporal dementia (also known as Multisystem proteinopathy (MSP)).Previous studies in drosophila models of VCP disease indicate treatment with VCP inhibitors mitigates disease pathology.Earlier-generation VCP inhibitors display off-target effects and relatively low therapeutic potency.New generation of VCP inhibitors needs to be evaluated in a mouse model of VCP disease.

In this study, we tested the safety and efficacy of a novel and potent VCP inhibitor, CB-5083 using VCP patient-derived myoblast cells and an animal model of VCP disease.Methods First, we analyzed the effect of CB-5083 in patient-derived myoblasts on the typical disease autophagy and TDP-43 profile by Western blot.Next, we determined the maximum tolerated dosage of CB-5083 in mice and treated the 2-month-old VCPR155H/R155H mice for 5 months with 15 mg/kg CB-5083.We analyzed motor function monthly by Rotarod; and we assessed the end-point blood toxicology, and the muscle and brain pathology, including autophagy and TDP-43 profile, using Western blot and immunohistochemistry.

We also treated 12-month-old VCPR155H/+ mice for 6 months and performed similar analysis.Finally, we assessed the potential side effects of CB-5083 on retinal function, using electroretinography in chronically treated VCPR155H/155H mice.Results In vitro analyses using patient-derived myoblasts confirmed that CB-5083 can modulate expression of the proteins in the autophagy pathways.We found that chronic CB-5083 treatment is well tolerated in the homozygous mice harboring patient-specific VCP variant, R155H, and can ameliorate the muscle pathology characteristic of the disease.

VCP-associated pathology biomarkers, such as elevated TDP-43 and p62 levels, were significantly reduced.Finally, to address the potential adverse effect of CB-5083 on visual function observed in a previous oncology clinical trial, we analyzed retinal function in mice treated with moderate doses of CB-5083 for 5 months and documented the absence of permanent ocular toxicity.Conclusions Altogether, these findings suggest click here that long-term use of CB-5083 by moderate doses is safe and can improve VCP disease-associated muscle pathology.Our results provide translationally relevant evidence that VCP inhibitors could be beneficial in the treatment of VCP disease.