VCP disease associated with Limb-Girdle Inclusion Body Myopathy (IBM), Paget's disease of the bone (PDB), Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) is caused by missense mutations of the valosin containing gene. In vitro assays of VCP mutants have shown enhanced ATPase activity, increased binding with its cofactors and reduced mitofuscin levels, providing evidence for a gain of function mechanism of disease. Zhang et al. (2017) have recently shown that NMS873 and ML240, earlier inhibitors of VCP were able to rescue disease phenotypes of mitochondrial dysfunction and cellular death in a drosophila model of VCP disease. These earlier inhibitors however were not suitable for clinical development and therefore new inhibitors were generated. CB-5083 is a reversible and competitive newer inhibitor of the AAA ATPase p97/VCP that preferentially targets the D2 ATPase domain and is highly specific making it ideal to probe the specific therapeutic benefit of normalizing the upregulated VCP activity in patients. Many types of cancer in humans are associated with elevated expression of VCP. Preclinical data in cellular and rodent cancer models provided the rationale for CB-5083 to be used for a Phase 1 trial by Cleave Biosciences in 84 subjects with solid tumors and multiple myeloma. CB-5083 has a clinically documented safety profile, was well tolerated at and below MTD doses in the phase I studies, however it was not successful in achieving the desired endpoints in the trial. Cleave Biosciences is not pursuing treatment of VCP inclusion body myopathy because of its relative rarity, however, have offered the drug for our proposed preclinical studies in order to obtain FDA approval for a clinical trial if the results are promising. The Kimonis lab has taken the lead in mechanistic and translational research in VCP disease and has generated a knock-in mouse model with the common R155H VCP mutation with autophagy, TDP-43 and mitochondrial pathology that resembles the human disease. Our hypothesis is that by inhibiting VCP activity to normal values we will reverse the typical disease pathology. Herein, we propose to test the potent VCP inhibitor CB-5083 in both patient derived myoblasts and the knock-in VCP mouse model. Thus, we propose these two aims:
Aim 1 : Correction of disease pathology in vitro in VCP disease patient myoblasts with CB- 5083 VCP inhibitor.
Aim 2 : Correction of muscle and spinal cord pathology in vivo in the heterozygous VCPR155H disease mouse model with CB-5083 VCP inhibitor. The long-term objective is to conduct a clinical trial of CB-5083 in patients with VCP disease that is safe and effective. 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. Successful therapeutics in VCP disease also has huge translational potential for more common diseases such as sporadic ALS, FTD and IBM with which it also shares common pathologies including disrupted autophagy and TDP-43 pathology.