Discovering Novel Therapeutics for Myotonic Dystrophy Type 1 (DM1)

肌营养不良是一个不同的集合~30遗传性疾病，涉及进行性肌肉 往往是致命的，往往是致命的。最常见的成人肌营养不良症是I型强直性肌营养不良症（DM 1 或MMD 1），其影响范围在1：8，000至1：22，000之间，导致严重残疾和缩短 寿命DM 1由DMPK基因的3 '-UTR（非翻译区）中扩增的CUG重复序列产生， 其特征在于有毒RNA分子的积累。目前还没有有效的治疗DM 1的方法。 部分是由于传统药物筛选测定的局限性。 Genma Biosciences（Genma Bio）开发了范式转换测定法，以实现其长期目标， 生产准备用于临床试验的先导DM 1治疗化合物。在这份提案中，Genma Bio将进一步 开发并验证其高通量全动物C. elegans筛选技术，并将其与 在完整的活体DM 1疾病模型中进行尖端的自动化运动监测。使用整个动物 该模型允许Genma Bio识别小分子命中，其中DM 1缺陷在原点得到校正 即RNA毒性在其天然环境中发生。命中应该包括化合物的类别 仅在完整的生物体中可接近，例如参与组织间信号传导的那些。另外通过 对于DM 1表型的恢复（如运动），Genma Bio并不假设特定的 靶向并可鉴定通过新机制起作用的候选药物， 紊乱具体地，使用这些测定法鉴定的DMl药物也可以有效对抗其他肌强直性疾病。 营养不良和约20种由RNA重复扩增引起的疾病，包括脊髓小脑共济失调8型， 10、12和36、脆性X综合征和肌萎缩性侧索硬化症（ALS）。的累积结果， Genma Bio的方法将是一个更广泛和更全面的高品质化合物比 通过传统的筛选方法鉴定，并具有最佳的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： 目的1：修改移动测定，使其与C. elegans DM 1 HTS平台。 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 挽救DM 1缺陷的分子。重要的是，这里的成功将导致药物发现管道 可推广到各种肌营养不良症。 该第一阶段提案将为第二阶段SBIR奠定基础，该阶段将包括一个更大规模的屏幕 以及对化合物的优先排序、哺乳动物试验和作用机制的阐明的后续行动。

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.