Pharmacokinetic assessment of peptide-based therapy HV-3 for the treatment of Huntington's disease

PROJECT SUMMARY/ABSTRACT JanusQ, LLC is a startup biotech company, spun out of Case Western Reserve University, and developing a peptide-based therapy for the treatment of mitochondrial dysfunction in Huntington’s Disease (HD). This neurological disorder affects roughly 30,000 diagnosed patients in the US, and an additional 150,000 are at risk. Currently, no proven, effective treatments for HD exists, and patients are relegated to therapies that alleviate involuntary muscle movement 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, resulting in reduced aberrant mitophagy and improved neuronal survival. When administered to HD animal models, HV-3 reduces behavioral and neuropathological phenotypes and improves survival. However, very little is known about the pharmacokinetics (PK) of HV-3, making it difficult to know whether or not this peptide is a suitable clinical candidate for the treatment of HD. The purpose of this SBIR grant is to ascertain the PK characteristics of HV-3, making it possible determine whether it will be necessary in future work to optimize the peptide to improve its PK characteristics. The project has two aims: (1) To develop bioanalytical techniques for lead peptide HV-3. Various methods for efficiently extracting HV-3 from plasma and brain tissue in high yield (andgt;80%) will be investigated. A method for the quantitation of HV-3 from various biological extracts will be developed and validated using tandem liquid chromatography mass spectroscopy. An acceptable method will need to quantitate HV-3 reliably at sub-micromolar concentrations. (2) To use the newly developed bioanalytical techniques to study the PK of HV-3 in vivo and ascertain its readiness as a candidate for HD therapy. Plasma and brain tissue concentrations of HV-3 will be determined at various time points after administration—via both intraperitoneal (IP) and subcutaneous (SQ) routes—at three separate doses. These results will directly address our central hypothesis: does HV-3 have the PK characteristics necessary for advancement to the clinic, or do specific properties require modification of the peptide? The proposed work is the next logical step toward the long-term goal of developing a peptide therapy to improve quality of life and survival of HD patients. The proposed work is commercially viable because current direct costs of HD patients in the US is about $1B/year. A treatment for HD that improves the survival and wellbeing of patients would reduce reliance on medical care givers and thus reduce overall medical cost. This SBIR grant will allow JanusQ to decide whether to develop HV-3 itself, or develop an optimized peptide as a breakthrough treatment for HD. Either approach would put JanusQ in a position to attract a commercialization partner.PROJECT NARRATIVE JanusQ, LLC is a startup biotech company that is developing a novel drug to treat Huntington’s Disease by preventing the mutant huntingtin protein from destroying mitochondria inside nerve cells of the brain. In mice, the drug markedly improves the course of the disease. This grant will allow JanusQ to develop methods for measuring blood and brain levels of the drug, and to determine whether the drug—as handled by the body—is already suitable for more advanced studies, or whether the drug will have to be optimized.