In vivo efficacy and in vitro toxicity assessment of peptide-based therapy HV-3 for the Treatment of Huntington's disease

PROJECT SUMMARY/ABSTRACT JanusQ, LLC—a startup biotech company spun out of Case Western Reserve University—is developing a peptide-based therapy for the treatment of mitochondrial dysfunction in Huntington’s Disease (HD). This neurological disorder affects 30,000 diagnosed patients in the US, with 150,000 more at risk. No proven, effective treatments for HD exist, and patients are relegated to therapies that lessen involuntary muscle movements and behavioral changes. Therapies that address the causative agent, the mutant huntingtin protein (mtHtt), have not yet seen success in the clinic, and the mechanism by which mtHtt leads to the disease state is poorly understood. Mutant huntingtin associates with mitochondria, triggering dysfunction that leads to neurotoxicity. In multiple HD models, valosin-containing protein (VCP) is recruited to mitochondria, where VCP associates with mtHtt and leads to excessive mitophagy and neuronal death. A newly designed peptide, HV-3, disrupts VCP-mtHtt interactions, reducing aberrant mitophagy and improving neuronal survival. In HD animal models, HV-3 reduces behavioral and neuropathological phenotypes and improves survival. JanusQ recently developed robust methods for quantitating HV-3 from plasma and brain tissue, and investigated the HV-3 disposition in vivo. The resulting pharmacokinetics (PK) and brain penetration support further development of the peptide. This SBIR grant takes the next logical steps by ascertaining HV-3’s potential for off-target effects and immunogenicity, as well as the potency of HV-3 in an HD mouse model. The project has two aims: (1) To perform preliminary safety/tox assessment of HV-3. The safety profile of HV-3 will be assessed using in-vitro and in-vivo assays. At this early stage, the focus will be on discovery-phase assays, with an assessment of potential off-target interactions, immunogenicity, blood chemistries, and liver/kidney toxicity. (2) To assess HV-3 dose-dependence using an in-vivo HD mouse model. The dose-dependent efficacy of HV-3 will be investigated in YAC128 HD mice by administering several doses SQ, starting at various stages of disease development. Validation assays will assess VCP-mtHtt interaction, VCP mitochondrial accumulation, mitochondrial function, survival of medium spiny neurons, mtHtt aggregation and retention of motor function during HD development. These results will directly address our central hypothesis that HV-3 has sufficient safety characteristics and potency for advancement to the clinic. Alternatively, which specific properties must be improved in future peptide optimization? The proposed work is central to JanusQ’s long-term goal of developing a peptide therapy to improve quality of life and survival of HD patients. The work is commercially viable because current direct costs of HD patients in the US is about $1B/year. An HD treatment that improves patient survival and wellbeing would reduce reliance on medical caregivers and thus reduce overall medical cost. This SBIR grant will allow JanusQ to form a strategy for further development of HV-3 itself, or for peptide optimization, as a breakthrough treatment for HD. This would enable JanusQ to attract an established pharmaceutical company as a discovery and commercialization partner.