Pharmacokinetic Assessment of Peptide-Based Therapy HV-3 for the Treatment of Huntington's Disease

项目总结/摘要 JanusQ，LLC是一家初创生物技术公司，从凯斯西储大学分拆出来， 用于治疗亨廷顿病（HD）中线粒体功能障碍的基于肽的疗法。这 在美国，神经系统疾病影响了大约30，000名确诊患者，另有150，000人处于危险之中。 目前，不存在针对HD的经证实的有效治疗，并且患者被降级到缓解HD的治疗。 不自主肌肉运动和行为变化。针对致病因子突变体的疗法 亨廷顿蛋白（mtHtt），尚未在临床上取得成功，mtHtt导致 对疾病状态知之甚少。突变亨廷顿蛋白与线粒体相关，引发功能障碍 导致神经中毒在多个HD模型中，含缬氨肽蛋白（VCP）被募集到线粒体 其中VCP与mtHtt结合并导致过度的线粒体自噬和神经元死亡。新设计的 肽HV-3破坏VCP：mtHtt相互作用，导致异常线粒体自噬减少和神经元凋亡改善。 生存当给予HD动物模型时，HV-3降低了行为和神经病理学表型 提高生存率。然而，对HV-3的药代动力学（PK）知之甚少， 以了解这种肽是否是治疗HD的合适临床候选物。这样做的目的 SBIR补助金是为了确定HV-3的PK特征，从而有可能确定它是否会被 在未来的工作中有必要优化肽以改善其PK特性。该项目有两个目标：（1） 建立先导肽HV-3的生物分析技术。各种有效提取HV-3的方法 将研究从血浆和脑组织中以高产率（>80%）分离的方法。HV-3的定量方法 将使用串联液相色谱质量 谱可接受的方法需要在亚微摩尔浓度下可靠地定量HV-3。（二） 利用新开发的生物分析技术研究HV-3在体内的PK，并确定其 准备好作为HD治疗的候选者。将测定HV-3的血浆和脑组织浓度 在给药后的不同时间点-通过腹膜内（IP）和皮下（SQ）途径-在三个 分开服用这些结果将直接解决我们的中心假设：HV-3是否具有PK特征 或者特定的性质需要肽的修饰？的 拟议的工作是朝着开发肽疗法的长期目标迈出的下一个合乎逻辑的步骤， HD患者的生活质量和生存率。由于目前的直接成本， 在美国，HD患者的治疗费用约为10亿美元/年。一种治疗HD的方法，可以改善患者的生存和健康状况， 病人可减少对医护人员的依赖，从而减低整体医疗成本。SBIR赠款将 让JanusQ决定是开发HV-3本身，还是开发优化的肽作为突破 HD的治疗。无论哪种方式，JanusQ都能吸引商业化合作伙伴。

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 (>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.