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

描述(申请人提供)：这项名为“治疗亨廷顿病的小分子p75神经营养素受体配体”的申请是对NINDS在翻译研究中的探索/发展项目(R21；计划公告：PAR-11-293)的响应。目前的提议将测试p75神经营养受体(P75NTR)的小分子非肽配体是否将成为治疗亨廷顿病(HD)的有效药物。HD是一种以进行性运动和认知障碍为特征的致命性神经退行性疾病。它是由编码亨廷顿(HTT)蛋白的基因突变引起的，这种突变导致纹状体中的中等刺神经元死亡。突变的HTT如何引起这种影响尚不清楚；然而，神经营养支持的丧失被认为起着关键和因果作用，p75NTR已被牵连。在HD患者和小鼠模型中，p75NTR在纹状体中表达上调，突变型HTT影响的通路共享p75NTR信号通路中的许多中央中间蛋白。我们的实验室已经开发出一流的小分子、口服生物可用p75NTR配体，这些配体可以抑制退行性信号，防止神经退行性变。一种主要配体LM11A-31正在通过我们目前的NIA U01计划进行开发。它已经在阿尔茨海默病(AD)小鼠模型上完成了多项成功的疗效试验，并在大鼠和狗身上进行了IND前研究。最近，该配体获得了FDA批准进行I期临床试验。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。这些拟议的研究将探讨LM11A-31治疗是否适用于HD。该建议的目的是：(I)确定LM11A-31是否可以减少HD表型快速发展的小鼠模型(R6/2)的认知和运动障碍以及神经病理；以及(Ii)确定LM11A-31是否可以减缓或防止另一种小鼠模型BACHD与HD相关的行为缺陷和神经病理特征的发展。这种小鼠出现HD表型的速度要慢得多，而且不那么严重，但它是这种疾病的更好的遗传复制，因此阳性结果可能更容易识别，更容易翻译到临床上。因此，靶向p75NTR可以抵消HD相关的有害信号，这是我们实验室唯一能够研究的HD治疗的全新假说。这些研究取得了积极的结果 将确定一种全新且可行的治疗策略，以减少目前无法治疗的许多HD表型(运动和认知障碍以及神经病理)。本R21提案旨在提供目标验证数据。在此获得的积极结果将是第一次证实p75NTR是HD模型的有效治疗靶点，并可以快速跟踪LM11A-31进入HD临床测试。

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.