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.

概括肌营养不良症1（DM1）是由CTG膨胀引起的常染色体显性疾病在DMPK基因的3'未翻译区域中重复道。 DM1中的主要治疗目标是突变的DMPK RNA编码膨胀的CUG重复序列（CugeXP），形成有毒的核内核内患者细胞中的聚集物或cugeXP焦点。我们已经开发了一种基于RNA的筛选策略识别小分子选择性地调节DMPK Cugexp RNA而不影响正常 DMPK成绩单。在2500种化合物的试验屏幕中，我们确定了一个原型小分子MDI16，有效地逆转了患者细胞和HSALR小鼠的关键DM1病理特征 DM1的模型。随着多个导线的识别大大提高了小分子的概率 DM1的治疗，我们使用此筛查策略来识别40,000种潜水员药物样的30次新型命中 MSSR-UCLA文库的小分子，该分子对负债进行了广泛的过滤。这与患者的MDI16相比细胞。重要的是，比较分析表明，我们的命中率与反义相当针对CugeXP的寡核苷酸，比发表在文学。在此应用程序中，我们建议通过排序效率来识别铅化合物，我们的热门面板的效力，选择性和安全性在逆转关键DM1病理特征，包括 CugeXP焦点的形成，异常RNA剪接，清晰的错误定位，CUGBP1和GSK3B升高 DM1患者肌细胞的水平。生化测定将用于确定作用机理排名最高的命中率，将测试其在反向DM1骨骼肌疾病中的体内效率在HSALR DM1小鼠模型中。击球的血脑屏障渗透将在新型的双性恋中进行测试转基因小鼠模型在大脑中表达cugexp焦点。因为没有有效的治疗方法 DM1，候选疗法化合物的鉴定为这种衰弱的患者提供了希望疾病。