Development of New Therapeutics for Amyotrophic Lateral Sclerosis

描述(申请人提供)：这个项目的目标是识别治疗肌萎缩侧索硬化症(ALS)的小分子，ALS是一种一致致命的、不可战胜的神经退行性运动神经元疾病。作为一种孤儿疾病，ALS通常不是制药行业的研究目标。因此，我们认为学术实验室有责任对减缓或逆转ALS运动神经元病理的分子进行药物发现计划。本提案通过四个项目努力做到这一点。每一种都是基于现有的体外细胞模型，该模型概括了ALS的关键病理生物学特征。这些模型筛选出以下化合物：(1)抑制突变的超氧化物歧化酶(MSOD1)诱导的细胞死亡；(2)下调mSOD1的表达；(3)促进主要星形胶质细胞谷氨酸转运体EAAT2的谷氨酸转运；(4)促进MS01蛋白的降解。每个基于细胞的模型都可以在高吞吐量屏幕上完全运行，这代表了我们工作战略的第一步。这四个项目分为如下两个连续阶段：早期阶段：目标1使用包含38,500个化合物的库(Mind库)进行高通量筛选(HTS)；目标2进行二次低通量筛选(LTS)分析，以验证HTS HITS，并进行体外毒理学和剂量反应研究；目标3利用结构活性研究和/或药物化学优化阳性化合物的化学结构。后期：目的4评价先导化合物的药代动力学(血脑屏障通透性)和安全性；目的5确定先导化合物(S)在改善ALS转基因小鼠模型运动神经元变性方面的疗效。在我们看来，这个项目与NINDS的使命高度相关。运动神经元变性的小分子疗法可能不仅对ALS有益，而且对其他神经退行性疾病也有好处，可能还会对中风或创伤性脑和脊髓损伤等情况有所帮助。外行总结：这是一项旨在发现治疗卢·格里克病的药物的提议，这种致命的疾病在很大程度上被大多数制药公司忽视；该计划中确定的药物可能会帮助其他大脑疾病。

DESCRIPTION (provided by applicant): The goal of this project is to identify small molecules that treat amyotrophic lateral sclerosis (ALS), a uniformly lethal, unbeatable neurodegenerative motor neurons disorder. As an orphan disease, ALS has not generally been a research target for the pharmaceutical industry. We therefore believe it is incumbent on academic laboratories to undertake drug discovery programs for molecules that slow or reverse motor neuron pathology in ALS. This proposal endeavors to do this through four projects. Each is based on an existing in vitro cell model that recapitulates key pathobiological features of ALS. These models screen for compounds that (1) inhibit cell death induced by mutant superoxide dismutase (mSOD1); (2) down-regulate expression of mSOD1; (3) enhance glutamate transport by the major astroglial glutamate transporter EAAT2; and (4) accelerate degradation of mS01 protein. Each cell-based model is fully operational in high throughput screens that represent the initial step of our working strategy. The four projects are divided into two sequential phases as follows: Early phase: Aim 1 Perform high throughput screens (HTS) using a library (MIND library) of 38,500 compounds; Aim 2 Perform secondary, low throughput screening (LTS) assays to validate HTS hits and perform in vitro toxicology and dose response studies; Aim 3 Optimize the chemical structure of positive compounds using structure activity studies and/or medicinal chemistry. Late phase: Aim 4 Evaluate the lead compounds for pharmacokinetic (permeation of the blood brain barrier) and safety properties; and Aim 5 Determine the efficacy of the lead compound(s) in ameliorating motor neuron degeneration in a transgenic mouse model of ALS. In our view, this project is highly relevant to the mission of the NINDS. Small molecules therapies for motor neuron degeneration are likely to be beneficial not only in ALS but also in other neurodegenerative disorders and potentially in conditions such as stroke or traumatic brain and spinal cord injury. Lay Summary: This is a proposal to discover drugs to treat Lou Gehrig's disease, a lethal disorder that is largely ignored by most drug companies; drugs identified in this program may help other brain diseases.