Discovering Novel Therapeutics for Myotonic Dystrophy Type 1 (DM1)

发现 1 型强直性肌营养不良 (DM1) 的新疗法

基本信息

批准号：
9409067
负责人：
Frederick M Ausubel
金额：
$ 15万
依托单位：
GENMA BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9409067
关键词：
Adult Affect Aging Amyotrophic Lateral Sclerosis Animal Model Animals Area Biological Biological Assay Biological Availability Biological Sciences Caenorhabditis elegans Cell physiology Cells Chemicals Clinical Trials Collection Complex Congestive Heart Failure Defect Development Disease Disease model Effectiveness Eligibility Determination Engineering Escherichia coli Foundations Fragile X Syndrome Functional disorder General Hospitals Genes Goals Hereditary Disease Human In Vitro Industrialization Industry Collaboration Lead Libraries Licensing Longevity Massachusetts Modeling Monitor Movement Muscle Weakness Muscular Dystrophies Myotonic Dystrophy Natural Products Nematoda Neurosciences Organism Pathway interactions Patients Pharmaceutical Preparations Phase Phenotype Positioning Attribute Preclinical Drug Evaluation Process Property Protocols documentation RNA RNA Processing RNA Splicing Research Signal Transduction Small Business Innovation Research Grant Spinocerebellar Ataxias Study models System Technology Testing Therapeutic Tissues Toxic effect Universities Untranslated Regions Validation base cell motility design disability drug candidate drug discovery effective therapy follow-up high throughput screening in vivo member muscle physiology novel novel therapeutics repaired restoration screening small molecule success

项目摘要

Muscular dystrophies are a diverse collection of ~30 genetic diseases that involve progressive muscle weakness and are often fatal. The most common adult muscular dystrophy is Myotonic Dystrophy Type I (DM1 or MMD1), which affects between 1:8,000 and 1:22,000 people, causing serious disabilities and a shortened lifespan. DM1 results from expanded CUG repeats in 3’-UTR (untranslated region) of the DMPK gene and is characterized by the accumulation of toxic RNA molecules. There are no effective treatments for DM1 in large part due to the limitations of traditional drug screening assays. Genma Biosciences (Genma Bio) has developed paradigm-shifting assays to enable its long-term goal of producing a lead DM1 therapeutic compound ready for clinical trials. In this proposal, Genma Bio will further develop and validate its high-throughput whole-animal C. elegans screening technology and merge it with cutting-edge automated movement monitoring in an intact, living DM1 disease model. Using a whole-animal model allows Genma Bio to identify small molecule hits in which DM1 defects are corrected at the point of origin of the disease, namely RNA toxicity occurring in its native context. Hits should include classes of compounds that are only accessible in an intact organism such as those involved in inter-tissue signaling. In addition, by assaying for the restoration of DM1 phenotypes such as movement, Genma Bio does not assume a specific target and can identify drug candidates acting by novel mechanisms potentially applicable to multiple related disorders. Specifically, DM1 drugs identified using these assays may also be effective against other myotonic dystrophies and the ~20 diseases caused by RNA repeat expansions including Spinocerebellar Ataxias types 8, 10, 12 and 36, Fragile X Syndrome, and Amyotrophic Lateral Sclerosis (ALS). The cumulative result of the Genma Bio approach will be a broader and more comprehensive set of high-quality compounds than would be identified through traditional screen approaches and that have optimal in vivo efficacy and favorable drug properties (low toxicity, good bioavailability). There are 2 specific aims: Aim 1: Modify the movement assays to be compatible with the C. elegans DM1 HTS platform. Aim 2: Perform a proof-of-principle screen using 10,000 known bioactive compounds to identify small molecules that rescue DM1 defects. Importantly, success here will result in a drug discovery pipeline generalizable to a variety of muscular dystrophies. This Phase I proposal will provide the foundation of a Phase II SBIR which will include a larger-scale screen and follow-up on prioritizing compounds, mammalian testing, and elucidation of the mechanism of action.

肌营养不良症是约 30 种涉及进行性肌肉萎缩的遗传性疾病的多样化集合最常见的成人肌营养不良症是 I 型强直性肌营养不良症 (DM1)。或 MMD1），影响 1:8,000 至 1:22,000 人，导致严重残疾并缩短 DM1 是由 DMPK 基因 3'-UTR（非翻译区）中扩展的 CUG 重复序列产生的。其特点是有毒 RNA 分子的积累，目前尚无针对大面积 DM1 的有效治疗方法。部分原因是传统药物筛选试验的局限性。 Gemma Biosciences (Genma Bio) 已经开发出范式转变，以实现其长期检测目标在这项提案中，Gemma Bio 将进一步生产用于临床试验的先导 DM1 治疗化合物。开发并验证其高通量全动物秀丽隐杆线虫筛选技术，并将其与使用完整的活体 DM1 疾病模型进行尖端的自动运动监测。该模型允许 Gemma Bio 识别小分子命中，其中 DM1 缺陷在起始点得到纠正疾病，即在其天然环境中发生的 RNA 毒性，命中应包括化合物类别。仅在完整的生物体中才能进入，例如参与组织间信号传导的生物体。在检测 DM1 表型（例如运动）的恢复时，Gemma Bio 并不假设特定的目标并可以识别通过可能适用于多种相关的新机制发挥作用的候选药物具体来说，使用这些测定法鉴定出的 DM1 药物也可能对其他肌强直症有效。营养不良和约 20 种由 RNA 重复扩增引起的疾病，包括脊髓小脑性共济失调 8 型、 10、12 和 36、脆性 X 综合征和肌萎缩侧索硬化症 (ALS)。 Gemma Bio 方法将是比现有方法更广泛、更全面的高质量化合物。通过传统筛选方法确定的最佳药物具有体内功效和有利的药物特性（低毒性、良好的生物利用度）有两个具体目标：目标 1：修改运动测定以与线虫 DM1 HTS 平台兼容。目标 2：使用 10,000 种已知的生物活性化合物进行原理验证筛选，以识别小分子重要的是，这里的成功将带来药物发现管道。可概括为多种肌营养不良症。第一阶段提案将为第二阶段 SBIR 奠定基础，其中将包括更大规模的屏幕以及对化合物优先顺序、哺乳动物测试和作用机制阐明的后续行动。