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）：我们将采用一种新的方法，通过专注于激活天然细胞保护机制自噬的药物来开发独特的ALS治疗剂。刺激自噬是治疗导致ALS的潜在神经变性的合理方法。它是神经元清除有毒错误折叠聚集蛋白的主要防御机制，有证据表明ALS中运动神经元（MN）的神经变性是由有毒，错误折叠，聚集形式的SOD 1，TDP 43和FUS的积累引起的。这些蛋白质的突变导致家族性ALS（fALS），并且这些蛋白质的过表达或异常翻译后修饰导致散发性ALS（sALS）中的MN变性。我们将开发有效刺激ALS MN中自噬的药物，以清除毒性蛋白质的积累，从而阻断神经变性和疾病进展，以治疗sALS患者。我们的合作者Finkbeiner博士先前确定了刺激神经元自噬并阻断ALS小鼠神经元模型中疾病进展的药物。他开发了神经元自噬诱导剂（NAIs）的药效团模型，这将帮助我们合理设计一个新的ALS治疗家族。为了促进这一发现计划，他还开发了ALS的创新模型，其中人类MN（i-MN）来自健康志愿者和fALS和sALS患者。使用称为机器人显微镜（RM）的自动成像和纵向分析系统，他是第一个显示ALS i-MN的疾病表型的人，因为他们比健康志愿者的i-MN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测定与人类ALS i-MN和最近开发的人i-星形胶质细胞从fALS患者，开发一个新的家庭NAI。使用药效团模型和迭代的药物化学过程，Nanosyn将完善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的增加效力和减少安全责任。Nanosyn将围绕模型的关键化学部分快速合成小的化合物库，这些化合物库将针对来自fALS和sALS患者的人类ALS i-MN模型进行筛选。该初步筛选将鉴定在促进人ALS i-MN的存活方面具有改善的效力和功效的NAI。结构-活性关系研究将进一步完善虚拟高通量筛选模型，以鉴定包含CNS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NAI，例如增加CNS可用性。在未来的2期SBIR研究中，将通过Finkbeiner博士开发的使用GFP-LC 3转基因小鼠的新方法，在体内测试电极导线诱导CNS自噬，并在SOD 1-G93 A转基因小鼠和过表达TDP 43（A315 T）的转基因小鼠中测试电极导线在逆转运动麻痹、增加存活率和减少运动神经元损失方面的疗效。