Small Molecule p75 Neurotrophin Receptor Ligand to Treat Huntington's Disease

小分子 p75 神经营养素受体配体治疗亨廷顿病

基本信息

批准号：
8583100
负责人：
FRANK M LONGO
金额：
$ 23.6万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8583100
关键词：
Adverse event Affect Alzheimer&apos s Disease Award Behavior Bioavailable Canis familiaris Cell Survival Characteristics Clinic Cognition Cognitive Cognitive deficits Corpus striatum structure Data Development Disease Disease model Dose Exons FDA approved Genes Genetic Grant Huntington Disease Huntington protein Impaired cognition Institution Intellectual Property Laboratories Lead Legal patent Length Ligands Link Longevity Mediating Motor Mus Mutation NGFR Protein NIH Program Announcements National Institute of Neurological Disorders and Stroke Nerve Degeneration Neurodegenerative Disorders Neurons Pathology Pathway interactions Patients Pharmaceutical Preparations Phase Phenotype Play Proteins Rattus Receptor Signaling Role Signal Pathway Signal Transduction Signaling Protein Testing Therapeutic Toxic effect Transgenic Mice Translational Research Treatment Efficacy United States National Institutes of Health Validation base cost effective design disease phenotype drug testing effective therapy efficacy trial good laboratory practice human Huntingtin protein improved motor deficit motor impairment mouse model mutant neuropathology novel prevent programs public health relevance receptor research clinical testing response small molecule therapeutic target transcriptional coactivator p75

项目摘要

DESCRIPTION (provided by applicant): This application titled "Small Molecule p75 Neurotrophin Receptor Ligand to Treat Huntington's Disease" is in response to NINDS Exploratory/Developmental Projects in Translational Research (R21; program announcement: PAR-11-293). The current proposal will test whether a small molecule, non-peptide ligand for the p75 neurotrophic receptor (p75NTR) will be an effective treatment for Huntington's disease (HD). HD is a fatal neurodegenerative disease characterized by progressive motor and cognitive deficits. It is caused by a mutation in the gene that encodes the Huntington (htt) protein, which causes medium spiny neurons in the striatum to die. How mutant htt causes this effect is unclear; however, loss of neurotrophic support is purported to play a key and causal role and p75NTR has been implicated. P75NTR is up-regulated in the striatum of HD patients and mouse models and many central intermediate proteins in p75NTR signaling pathways are shared by pathways affected by mutant htt. Our laboratory has developed first-in-class small molecule, orally bioavailable p75NTR ligands that inhibit degenerative signaling, and prevent neurodegeneration. One lead ligand, LM11A-31, is well into development via our current NIA U01 program. It has completed multiple successful efficacy trials in Alzheimer disease (AD) mouse models and pre-IND studies in rats and dogs. Recently, the ligand received FDA approval for phase I clinical testing. Intellectual property for the compound is intact and owned by UNC and UCSF. These proposed studies will examine whether treatment with LM11A-31 is applicable to HD. The aims of the proposal are to: (i) determine whether LM11A-31 will reduce cognitive and motor deficits as well as neuropathology in a mouse model (R6/2) that develops the HD phenotype rapidly and is therefore cost effective and ideal for PK/PD studies; and ii) determine if LM11A-31 will slow or prevent the development of HD-related behavior deficits and neuropathological features in another mouse model, BACHD. This mouse develop an HD phenotype much slower and less severely but is a better genetic replicate of the disease, thus positive results may be easier to discern and be more readily translatable to the clinic. Thus, targeting p75NTR could offset HD-related deleterious signaling, an entirely new hypothesis for HD treatment that our laboratory is uniquely able to investigate. Positive results in these studies will identify an entirely novel and feasible therapeutic strategy for reducing numerous HD phenotypes (motor and cognitive impairments as well as neuropathology), which are currently untreatable. This R21 proposal is designed to provide target validation data. Positive results obtained here would be the first validation that p75NTR is an effective therapeutic target for an HD model and could fast track LM11A-31 into HD clinical testing.

描述（由申请人提供）：本申请题为“治疗亨廷顿病的小分子 p75 神经营养蛋白受体配体”，是对 NINDS 转化研究探索/开发项目（R21；计划公告：PAR-11-293）的回应。目前的提案将测试 p75 神经营养受体 (p75NTR) 的小分子非肽配体是否能有效治疗亨廷顿病 (HD)。 HD 是一种致命的神经退行性疾病，其特征是进行性运动和认知缺陷。它是由编码亨廷顿 (htt) 蛋白的基因突变引起的，该突变会导致纹状体中的中型多棘神经元死亡。突变体 htt 如何引起这种效应尚不清楚；然而，据称神经营养支持的丧失起着关键的因果作用，并且 p75NTR 也参与其中。 P75NTR 在 HD 患者和小鼠模型的纹状体中上调，p75NTR 信号通路中的许多中心中间蛋白与受突变 htt 影响的通路共享。我们的实验室开发了一流的小分子、口服生物可利用的 p75NTR 配体，可抑制退行性信号传导并预防神经退行性变。一种先导配体 LM11A-31 正在通过我们当前的 NIA U01 计划进行顺利开发。它已在阿尔茨海默病 (AD) 小鼠模型中成功完成了多项功效试验，并在大鼠和狗中完成了 IND 前研究。最近，该配体获得 FDA 批准进行 I 期临床测试。该化合物的知识产权完好无损，归北卡罗来纳大学和加州大学旧金山分校所有。这些拟议的研究将检验 LM11A-31 治疗是否适用于 HD。该提案的目的是：(i) 确定 LM11A-31 是否会减少快速发展 HD 表型的小鼠模型 (R6/2) 的认知和运动缺陷以及神经病理学，因此具有成本效益且是 PK 的理想选择/PD研究； ii) 确定 LM11A-31 是否会减缓或阻止另一种小鼠模型 BACHD 中 HD 相关行为缺陷和神经病理学特征的发展。这只小鼠形成HD表型的速度要慢得多，也不太严重，但它是该疾病的更好的遗传复制品，因此阳性结果可能更容易辨别，也更容易转化为临床。因此，靶向 p75NTR 可以抵消 HD 相关的有害信号传导，这是我们实验室唯一能够研究的 HD 治疗的全新假设。这些研究的积极结果将确定一种全新且可行的治疗策略，用于减少目前无法治疗的众多 HD 表型（运动和认知障碍以及神经病理学）。此 R21 提案旨在提供目标验证数据。这里获得的阳性结果将首次验证 p75NTR 是 HD 模型的有效治疗靶点，并且可以快速将 LM11A-31 纳入 HD 临床测试。