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

描述（由申请人提供）：这份题为“小分子p75神经营养因子受体配体治疗亨廷顿病”的申请是对NINDS转化研究探索性/发展性项目（R21；项目公告：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，以进行性运动和认知障碍为特征。它是由编码亨廷顿蛋白（htt）的基因突变引起的，这种突变会导致纹状体中的中等棘神经元死亡。突变的htt是如何引起这种影响的尚不清楚；然而，神经营养支持的丧失据称起着关键的因果作用，p75NTR已被牵连其中。P75NTR在HD患者和小鼠的纹状体中上调，并且P75NTR信号通路中的许多中心中间蛋白与突变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正在通过我们目前的NIA U01项目进行开发。它已经在阿尔茨海默病（AD）小鼠模型中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的I期临床试验批准。该化合物的知识产权是完整的，由北卡罗来纳大学和加州大学旧金山分校拥有。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）中的认知和运动缺陷以及神经病理学，因此具有成本效益，是PK/PD研究的理想选择；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特征的发展。这种小鼠发展HD表型的速度要慢得多，也不那么严重，但它是一种更好的疾病基因复制，因此积极的结果可能更容易辨别，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，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

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.