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

基本信息

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
项目类别：
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

项目摘要

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治疗剂，通过专注于激活天然细胞保护机制自动噬菌体的药物。刺激自噬是一种逻辑方法，用于治疗导致ALS的潜在神经变性。这是神经元去除毒性错误折叠蛋白质的主要防御机制，并且有证据表明，ALS中运动神经元（MN）的神经变性是由有毒，错误折叠的，SOD1，TDP43和FUS的有毒，错误折叠，聚集的形式的堆积引起的。这些蛋白质中的突变引起家族性ALS（fals），这些蛋白质的过表达或异常的翻译后修饰导致零星ALS（SALS）的MN变性。我们将开发有效刺激ALS MN自噬的药物，以消除有毒蛋白的积累，以阻止神经退行性的进展和疾病进展以治疗SALS患者。我们的合作者Finkbeiner博士先前鉴定出刺激神经元中自噬的药物，并阻止ALS的鼠神经元模型中的疾病进展。他开发了神经元自噬诱导剂（NAIS）的药效团模型，该模型将帮助我们合理设计一个新的一流ALS Therapeutics家族，以促进该发现程序，他还开发了具有人类MNS（I-MN）的ALS创新模型，该模型来自健康的志愿者和Fals和Sals。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疾病表型的人，因为它们的死亡风险比健康志愿者的I-MN更大。该疾病表型提供了一个可靠的，可确定的生理终点，用于测试新药在治疗ALS方面的功效。我们将与人类I-MNS一起使用这些新型体外测定，并最近从伪装患者中开发了人类的I-心细胞，以开发一个新的NAI家族。使用药效团模型和迭代药物化学过程，Nanosyn将完善NAI药效团模型，以鉴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，它通过增加效力和降低的安全责任来确定NAI的可行性。 Nanosyn将迅速合成该模型关键化学部分的小型库，这些库将与来自FALS和SALS患者的人类I-MN模型进行筛选。这项主要筛查将确定NAI具有提高效力和功效促进人类I-MN的生存的NAI。结构活性关系研究将进一步完善虚拟高通量筛选的模型，以识别独特的化合物，这些化合物融合了CNS-挑剔的碎片，以选择具有所需特性的NAI，以治疗慢性神经变性疾病，例如增加CNS的可用性。 Finkbeiner博士开发的一种新型方法将在VIVO中的未来2阶段研究中进行测试，以在CNS中诱导自噬，该方法使用GFP-LC3转基因小鼠并在SOD1-G93A转基因小鼠和转型TDP43（A315T）中的效率（A315T）中的速度增长，并在Recorsy parement parementy parement and Cornorsy中，在SOD1-G93A转基因小鼠中的功效损失。