Small molecule neuronal autophagy inducers designed to block neurodegeneration to

小分子神经元自噬诱导剂旨在阻止神经变性

• 批准号: 8761498
• 负责人: STEVEN M FINKBEINER
• 金额: $ 29.53万
• 依托单位: NANOSYN, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761498
• 关键词: Affect; Amyloid; Animal Disease Models; Applications Grants; Astrocytes; Autophagocytosis; Biological Assay; Cell Nucleus; Cessation of life; Chemical Structure; Chemicals; Chronic; Clinical; Corpus striatum structure; Cytoplasmic Inclusion; Data; Defense Mechanisms; Development; Disease; Disease Progression; Drug Targeting; Elements; Family; Foundations; Future; Genes; Goals; Human; Huntington Disease; Image Analysis; Inclusion Bodies; Institutes; Libraries; Microscopy; Modeling; Molecular Target; Motor; Motor Neurons; Mus; Muscular Atrophy; Mutation; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Neuroprotective Agents; Paralysed; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Physiological; Post-Translational Protein Processing; Preclinical Testing; Primary Lateral Sclerosis; Process; Property; Proteins; Publishing; RNA biosynthesis; Research; Respiratory Failure; Risk; Robotics; Rodent; Role; Safety; Series; Small Business Innovation Research Grant; Structure; Structure-Activity Relationship; System; Technology; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Toxicology; Transgenic Mice; base; design; disease phenotype; drug efficacy; healthy volunteer; high risk; high throughput screening; human Huntingtin protein; improved; in vitro Assay; in vivo; induced pluripotent stem cell; innovation; longitudinal analysis; model design; motor neuron degeneration; mutant; nervous system disorder; neuron loss; novel; novel strategies; overexpression; pharmacophore; phase 2 study; pre-clinical; prevent; programs; protein aggregate; prototype; public health relevance; screening; small molecule; virtual

DESCRIPTION (provided by applicant): We will employ a novel approach to develop unique ALS therapeutics by focusing on drugs that activate a natural cellular protective mechanism, autophagy. Stimulating autophagy is a logical approach to treat the underlying neurodegeneration that causes ALS. It is the prime defense mechanism that neurons have for removing toxic misfolded aggregated proteins, and there is evidence that neurodegeneration of motor neurons (MNs) in ALS is caused by the buildup of toxic, misfolded, aggregated forms of SOD1, TDP43 and FUS. Mutations in these proteins cause familial ALS (fALS), and overexpression or abnormal post-translational modification of these proteins leads to MN degeneration in sporadic ALS (sALS). We will develop drugs that effectively stimulate autophagy in ALS MNs to remove the buildup of toxic proteins to block neurodegeneration and disease progression to treat sALS patients. Our collaborator, Dr. Finkbeiner, previously identified drugs that stimulate autophagy in neurons and block disease progression in murine neuronal models of ALS. He developed a pharmacophore model of neuronal autophagy inducers (NAIs) that will help us rationally design a new family of first-in-class ALS therapeutics To facilitate this discovery program, he also developed innovative models of ALS with human MNs (i-MN) derived from healthy volunteers and patients with fALS and sALS. Using an automated imaging and longitudinal analysis system called robotic microscopy (RM) he was the first to show a disease phenotype for ALS i-MNs in that they had a greater risk of death than i-MNs from healthy volunteers. This disease phenotype provides a robust, definable physiological endpoint to test new drugs for efficacy in treating ALS. We will use these novel in vitro assays with human ALS i-MNs and recently developed human i-astrocytes from patients with fALS, to develop a new family of NAIs. Using the pharmacophore model and an iterative medicinal chemistry process, Nanosyn will refine the NAI pharmacophore model to identify minimal chemical structures needed to induce autophagy. Preliminary studies have already established the feasibility of this approach by identify NAI's with increased potency and reduced safety liabilities. Nanosyn will rapidly synthesize small libraries of compounds around key chemical moieties of the model that will be screened against the human ALS i-MN models from patients with fALS and sALS. This primary screening will identify NAIs with improved potency and efficacy in promoting survival of human ALS i-MNs. Structure-activity relationship studies will further refine the model for virtual high-throughput screening to identify unique compounds that incorporate CNS-privileged pieces to select for NAIs with desired properties for treating a chronic neurodegeneration disease, such as increased CNS availability. Leads will be tested in future Phase 2 SBIR studies in vivo for inducing autophagy in the CNS by a novel approach developed by Dr. Finkbeiner that uses GFP-LC3 transgenic mice and for efficacy in SOD1-G93A transgenic mice and transgenic mice over- expressing TDP43 (A315T) in reversing motor paralysis, increasing survival, and reducing motor neuron loss.

描述（由申请人提供）：我们将采用一种新颖的方法来开发独特的ALS治疗药物，专注于激活自然细胞保护机制——自噬的药物。刺激自噬是治疗导致肌萎缩侧索硬化症的潜在神经变性的一种合乎逻辑的方法。这是神经元清除有毒的错误折叠聚集蛋白的主要防御机制，有证据表明，ALS患者运动神经元（MNs）的神经退行性变是由有毒的、错误折叠的、聚集形式的SOD1、TDP43和FUS的积累引起的。这些蛋白的突变导致家族性ALS (fALS)，这些蛋白的过表达或异常翻译后修饰导致散发性ALS （sALS）的MN变性。我们将开发能够有效刺激ALS MNs细胞自噬的药物，以清除积聚的有毒蛋白质，阻止神经退行性变和疾病进展，从而治疗ALS患者。我们的合作者Finkbeiner博士之前在ALS小鼠神经元模型中发现了刺激神经元自噬和阻止疾病进展的药物。他开发了神经元自噬诱导剂（NAIs）的药效团模型，这将帮助我们合理地设计一个新的同类ALS治疗药物家族。为了促进这一发现计划，他还开发了来自健康志愿者和fALS和sALS患者的人类MNs （i-MN）的ALS创新模型。利用一种称为机器人显微镜（RM）的自动成像和纵向分析系统，他是第一个显示ALS i-MNs的疾病表型的人，因为他们比健康志愿者的i-MNs有更大的死亡风险。这种疾病表型提供了一个强大的，可定义的生理终点，以测试新药治疗ALS的疗效。我们将使用这些新的体外检测人类ALS i-MNs和最近从fALS患者身上开发的人类i-星形胶质细胞，以开发一个新的NAIs家族。利用药效团模型和迭代药物化学过程，Nanosyn将改进NAI药效团模型，以确定诱导自噬所需的最小化学结构。初步研究已经确定了这种方法的可行性，确定了NAI的效力增加和安全责任减少。Nanosyn将快速合成围绕模型关键化学部分的小化合物文库，这些化合物将用于筛选来自fALS和sALS患者的ALS i-MN模型。这项初步筛选将确定在促进人类ALS i-MNs生存方面具有更高效力和疗效的nai。结构-活性关系研究将进一步完善虚拟高通量筛选模型，以识别包含中枢神经系统特权片段的独特化合物，以选择具有治疗慢性神经退行性疾病所需特性的NAIs，例如增加中枢神经系统可用性。在未来的2期SBIR研究中，我们将通过芬克贝纳博士开发的一种新方法（使用ggp - lc3转基因小鼠）来测试导联在体内诱导中枢神经系统自噬的效果，并在SOD1-G93A转基因小鼠和过表达TDP43 （A315T）的转基因小鼠中测试导联在逆转运动麻痹、提高存活率和减少运动神经元损失方面的功效。