Inclusion Body Myopathy associated with Paget’s disease of the bone, frontotemporal dementia (IBMPFD), and amyotrophic lateral sclerosis (ALS) is a rare syndromic disease caused by gain-of-function variants in the Valosin Containing Protein (VCP) gene. VCP disease variants affect the consolidation of aggregate-prone proteins into inclusion bodies and disrupt the autophagic degradation of ubiquitylated proteins. There is currently no treatment for this progressive disease associated with early demise resulting from proximal limb girdle and respiratory muscle weakness. Antisense Oligonucleotide (ASO) technology has emerged as a powerful direct therapeutic alternative to conventional small molecule approaches or gene replacement strategies for the treatment of genetic disorders. We hypothesize that inhibiting VCP with ASO technology will ameliorate the clinical manifestations of this debilitating disease by normalizing VCP activity, thus improving pathology from the disrupted pathways.
In this study, we assessed the effect of ASOs specifically targeting the human VCP gene in the patient (R155H) iPSC-derived skeletal muscle progenitor cells (SMPCs). ASOs were well tolerated up to 5 µM concentration and significantly reduced VCP mRNA and protein expression by ~ 50%. Additionally, TDP 43 mRNA and protein expression was reduced by 50% and 60 % upon ASO treatment compared to untreated cells.
We then treated the transgenic mouse model of VCP disease which overexpresses the humanized VCP gene with the severe A232E mutation, with weekly subcutaneous injections starting from 6 months of age for 3 months. ASO2 demonstrated tolerability in VCP transgenic mice and showed over 50% knockdown of VCP at the mRNA level and the protein level compared to control ASO. We found improvement in the autophagy markers and reduction in TDP-43 expression, hallmarks of VCP disease. ASO treatment also decreased the number of central nuclei in myofiber in VCPA232E mice as compared to control ASO treatment. ASO2-treated VCP A232E mice showed improvements in motor testing studies including the inverted screen and Rotarod tests compared to mice treated with control ASO. These results targeting VCP in SMPCs and mice with the VCP A232E variant suggest that ASOs targeting VCP could be beneficial in preventing the progression of the myopathy in patients with VCP MSP1.