Small molecule therapeutics for myotonic dystrophy type 1

1 型强直性肌营养不良的小分子疗法

基本信息

批准号：
10583984
负责人：
LUCIO COMAI
金额：
$ 41.25万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-15 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583984
关键词：
3&apos Untranslated Regions Affect Antisense Oligonucleotide Therapy Antisense Oligonucleotides Biochemical Biological Assay Biological Products Biology Blood - brain barrier anatomy Brain Budgets CUG repeat Cells Central Nervous System Chemicals Clinical Trials Complex Cyclic AMP-Dependent Protein Kinases Data Defect Development Disease Dose Drug Combinations Exhibits Genes Genetic Diseases In Vitro Lead Libraries Link Literature Measures Mediating Messenger RNA Molecular Muscle Myoblasts Myopathy Myotonic Dystrophy Myotonic dystrophy type 1 Pathologic Pathology Patients Penetrance Permeability Pharmaceutical Preparations Phenotype Physiological Play Probability Protein Family Proteins Publishing RNA RNA Splicing Role Safety Skeletal Muscle System Testing Therapeutic Time Toxic effect Transcript Transgenic Mice Transgenic Organisms absorption autosome candidate identification comparative design drug candidate drug development effective therapy in vivo in vivo evaluation inhibitor insight mouse model mutant novel overexpression prototype response screening small molecule small molecule therapeutics therapeutic candidate therapeutic target

项目摘要

Summary Myotonic dystrophy 1 (DM1) is an autosomal dominant disorder resulting from the expansion of a CTG repeat tract in the 3’ untranslated region of the DMPK gene. The primary therapeutic target in DM1 is the mutant DMPK RNA encoding expanded CUG repeats (CUGexp), which forms toxic intra-nuclear aggregates or CUGexp foci in patient cells. We have developed an RNA-based screening strategy to identify small molecules that selectively modulate the DMPK CUGexp RNA without affecting the normal DMPK transcript. In a pilot screen of 2,500 compounds we identified a prototype small molecule MDI16, which effectively reverses critical DM1 pathological features in both patient cells and in the HSALR mouse model of DM1. As identification of multiple leads greatly enhances the probability of a small molecule therapy for DM1, we used this screening strategy to identify 30 novel hits from 40,000 diverse drug-like small molecules of the MSSR-UCLA library, which has undergone extensive filtering against liabilities. This panel of hits show better safety and efficacy in reducing CUGexp foci when compared to MDI16 in patient cells. Importantly, comparative analysis demonstrates that our hits perform on par with antisense oligonucleotides directed against CUGexp and better than DM1 small molecule therapeutics published in the literature. In this application we propose to identify lead compounds by rank-ordering the efficacy, potency, selectivity and safety of our hit panel in reversing key DM1 pathological features including the formation of CUGexp foci, aberrant RNA splicing, SHARP mis-localization, elevated CUGBP1 and GSK3b levels in DM1 patient myoblasts. Biochemical assays will be used to determine the mechanism of action of top-ranked hits, which will be tested for their in vivo efficacy in reversing DM1 skeletal muscle disease in the HSALR DM1 mouse model. Blood brain barrier penetrance of the hits will be tested in a novel bi- transgenic mouse model that expresses CUGexp foci in the brain. As there is no effective treatment for DM1, the identification of candidate therapeutic compounds offers hope for patients with this debilitating disease.

概括强直性肌营养不良 1 (DM1) 是一种常染色体显性遗传疾病，由 CTG 扩张引起 DMPK 基因 3' 非翻译区的重复序列 DM1 的主要治疗靶点是突变 DMPK RNA 编码扩展的 CUG 重复序列 (CUGexp)，形成有毒的核内我们开发了一种基于 RNA 的筛选策略来检测患者细胞中的聚集体或 CUGexp 病灶。识别选择性调节 DMPK CUGexp RNA 而不影响正常细胞的小分子在对 2,500 种化合物的初步筛选中，我们鉴定出了原型小分子 MDI16，有效逆转患者细胞和 HSALR 小鼠中关键的 DM1 病理特征 DM1 的模型，由于多个先导的识别大大提高了小分子的概率。 DM1 疗法中，我们使用这种筛选策略从 40,000 种不同的药物中鉴定出 30 种新药 MSSR-UCLA 库的小分子，该库经过了广泛的负债过滤。与 MDI16 相比，一系列命中显示在减少 CUGexp 病灶方面具有更好的安全性和功效重要的是，我们的命中结果与反义细胞的性能相当的比较分析。针对 CUGexp 的寡核苷酸，优于 DM1 小分子疗法，发表于在本申请中，我们建议通过对功效进行排序来识别先导化合物，我们的HIT面板在逆转DM1关键病理特征方面的效力、选择性和安全性，包括 CUGexp 灶的形成、RNA 剪接异常、SHARP 错误定位、CUGBP1 和 GSK3b 升高 DM1 患者成肌细胞中的水平将用于确定作用机制。排名靠前的热门产品，将测试其逆转 DM1 骨骼肌疾病的体内功效在 HSALR DM1 小鼠模型中，将在一种新型双-中测试血脑屏障的穿透性。大脑中表达 CUGexp 灶的转基因小鼠模型，因为目前尚无有效的治疗方法。 DM1，候选治疗化合物的鉴定为患有这种衰弱症状的患者带来了希望疾病。