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

• 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
• 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' 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

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“小分子p75神经营养因子受体配体治疗亨廷顿病”，是对NINDS转化研究探索/开发项目（R21;计划公告：PAR-11-293）的回应。目前的提议将测试p75神经营养受体（p75 NTR）的小分子非肽配体是否能有效治疗亨廷顿病（HD）。HD是一种以进行性运动和认知缺陷为特征的致死性神经退行性疾病。它是由编码亨廷顿（htt）蛋白的基因突变引起的，该基因突变导致纹状体中的中型多刺神经元死亡。突变htt如何引起这种效应尚不清楚，然而，神经营养支持的丧失据称发挥关键和因果作用，p75 NTR已被牵连。P75 NTR在HD患者和小鼠模型的纹状体中上调，并且p75 NTR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。我们的实验室已经开发出一流的小分子，口服生物可利用的p75 NTR配体，抑制退行性信号传导，防止神经退行性变。一种先导配体LM 11 A-31正在通过我们目前的NIA U 01计划进行开发。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，并在大鼠和犬中完成了IND前研究。最近，该配体获得FDA批准进行I期临床试验。该化合物的知识产权是完整的，由UCSF和UCSF拥有。这些拟议的研究将检查LM 11 A-31治疗是否适用于HD。（i）确定LM 11 A-31是否将减少小鼠模型（R6/2）中的认知和运动缺陷以及神经病理学，所述小鼠模型（R6/2）快速发展HD表型并且因此是成本有效的并且对于PK/PD研究是理想的;和ii）确定LM 11 A-31是否将减缓或预防另一小鼠模型中HD相关行为缺陷和神经病理学特征的发展，BACHD该小鼠发展HD表型慢得多且不太严重，但是该疾病的更好遗传复制，因此阳性结果可能更容易辨别并且更容易转化为临床。因此，靶向p75 NTR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 将确定一种全新的可行的治疗策略，用于减少目前无法治疗的多种HD表型（运动和认知障碍以及神经病理学）。本R21提案旨在提供目标验证数据。在此获得的阳性结果将首次验证p75 NTR是HD模型的有效治疗靶标，并且可以快速跟踪LM 11 A-31进入HD临床测试。