Abstract
BackgroundPathogenic gain of function variants in Valosin-containing 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.MethodsFirst, 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.ResultsIn 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.ConclusionsAltogether, these findings suggest 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.
Highlights
Multisystem proteinopathy caused by variants in the Valosin-containing protein (VCP) gene is characterized by inclusion body myopathy, Paget disease of the bone, and frontotemporal dementia
TDP-43 was highly expressed in the nucleus of both cell lines, cytoplasmic TDP-43 was found only in the VCP disease patientderived myoblasts in 2% to 15% of the cells (Fig. 1A, Additional file 1: Fig. S1C)
Myofiber pathology was alleviated in VCPR155H/R155H mice with CB‐5083 treatment To assess the effect of CB-5083 on myofiber morphology in VCPR155H/R155H mice, we examined the gross structures of myofibers from mice quadriceps with Hematoxylin and eosin (H&E) staining
Summary
Multisystem proteinopathy caused by variants in the VCP gene is characterized by inclusion body myopathy, Paget disease of the bone, and frontotemporal dementia. VCP disease is a rare neuromuscular disease that has been diagnosed in several hundred people worldwide [1,2,3] Among these patients, myopathy occurs in 80–90% of individuals with a mean onset of 42 years of age [2, 4]. Paget disease of bone occurs in 49% of patients with a similar age of onset as myopathy and affects the vertebral column, pelvis, scapulae, and skull [5]. Pathogenic gain of function variants in Valosin-containing protein (VCP) cause a unique disease characterized by inclusion body myopathy with early-onset Paget disease of bone and frontotemporal dementia ( known as Multisystem proteinopathy (MSP)). 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
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