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

用于治疗亨廷顿病的基于肽的疗法 HV-3 的药代动力学评估

基本信息

批准号：
10078211
负责人：
Andrew Loring Schilb
金额：
$ 24.09万
依托单位：
JANUSQ, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10078211
关键词：
Address Affect Amino Acids Animal Disease Models Behavioral Biological Biotechnology Blood Brain Caregivers Cell Death Clinic Dependence Development Diagnosis Direct Costs Disease Disease model Dose Drug Kinetics Functional disorder Future Goals Grant Half-Life Huntington Disease Huntington gene Huntington protein Individual Inherited Lead Measures Medical Medical Care Costs Methods Mitochondria Modification Movement Mus Nerve Degeneration Neurodegenerative Disorders Neurons Outcome Patients Peptides Personal Satisfaction Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Plasma Positioning Attribute Preparation Property Proteins Quality of life Readiness Risk Route Small Business Innovation Research Grant Smooth Muscle Symptoms Techniques Testing Time Universities Work absorption base brain cell brain tissue clinical candidate commercial application commercialization design effective therapy improved in vivo inhibitor/antagonist intraperitoneal liquid chromatography mass spectroscopy mitochondrial dysfunction mutant nervous system disorder neuron loss neuronal survival neurotoxicity novel therapeutics peptide drug pharmacokinetic characteristic prevent recruit subcutaneous success valosin-containing protein

项目摘要

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.

项目概要/摘要 JanusQ, LLC 是一家初创生物技术公司，从凯斯西储大学分离出来，致力于开发一种基于肽的疗法，用于治疗亨廷顿病（HD）的线粒体功能障碍。在美国，神经系统疾病影响着大约 30,000 名确诊患者，另有 150,000 人面临风险。目前，尚无经过证实的有效治疗 HD 的方法，患者需要接受能够缓解 HD 症状的治疗方法。针对致病因子（突变体）的治疗。亨廷顿蛋白（mtHtt），尚未在临床上取得成功，mtHtt导致的机制人们对这种疾病状态知之甚少，突变的亨廷顿蛋白与线粒体有关，会引发功能障碍。在多种 HD 模型中，含有缬氨肽的蛋白 (VCP) 被募集到线粒体中，从而导致神经毒性。其中VCP与mtHtt相关并导致过度线粒体自噬和神经元死亡。肽 HV-3 破坏 VCP:mtHtt 相互作用，从而减少异常线粒体自噬并改善神经元当给予HD动物模型时，HV-3可降低行为和神经病理表型。然而，人们对 HV-3 的药代动力学 (PK) 知之甚少，这使得研究变得困难。了解该肽是否适合临床治疗 HD。 SBIR拨款是为了确定HV-3的PK特性，从而可以确定它是否会被在未来的工作中需要优化肽以改善其 PK 特性，该项目有两个目标：（1）开发先导肽 HV-3 的生物分析技术，以有效提取 HV-3。将研究从血浆和脑组织中高产率 (>80%) 定量 HV-3 的方法。将使用串联液相色谱质量法开发和验证来自各种生物提取物的可接受的方法需要在亚微摩尔浓度下可靠地定量 HV-3 (2)。利用新开发的生物分析技术研究HV-3的体内PK并确定其作用将确定 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。是进入临床所必需的，还是需要对肽进行特定性质的修饰？拟议的工作是实现开发肽疗法以改善病情的长期目标的下一个合乎逻辑的步骤由于目前的直接成本，拟议的工作在商业上是可行的。美国 HD 患者的治疗费用约为 1B 美元/年，可提高患者的生存率和福祉。患者将减少对医疗护理人员的依赖，从而降低总体医疗费用。让JanusQ决定是自行开发HV-3，还是开发优化的肽作为突破口这两种方法都可以让 JanusQ 吸引商业化合作伙伴。