Center for Research Translation of Systemic Exon-skipping in Muscular Dystrophy

肌营养不良症系统性外显子跳跃研究转化中心

• 批准号: 8330812
• 负责人: ERIC P. HOFFMAN
• 金额: $ 157.1万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-09 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8330812
• 关键词: Becker Muscular Dystrophy; Biological Assay; Canis familiaris; Cells; Clinical Trials; Complex; Consensus; Diagnostic; Drug Approval; Duchenne muscular dystrophy; Dystrophin; Exons; Gene Delivery; Gene Proteins; Genes; Goals; Human; In Vitro; Methods; Modeling; Molecular; Muscle; Muscular Dystrophies; Mutation; Natural History; Patients; Pharmaceutical Preparations; Procedures; Production; Proteins; RNA Splicing; Reading; Reporting; Research; Safety; System; Terminator Codon; Testing; Therapeutic; Transcript; Translational Research; Translations; Viral Vector; cell bank; clinical efficacy; cost; drug development; exon skipping; functional outcomes; gene therapy; in vivo; innovation; mouse model; mutant; pre-clinical; programs; protein function; repaired; small molecule; stem cell therapy

DESCRIPTION (provided by applicant): The identification of the Duchenne muscular dystrophy gene and protein in the late 1980's led to high hopes of rapid translation to rational therapeutics. Early reports of delivering new functional genes to mouse model muscle via gene therapy and stem cell therapy fueled this hope. However, these same studies illuminated the very high hurdles facing human applications. Insufficient therapeutic material (cells, viral vectors), challenges in systemic delivery, and immunological hurdles all remain barriers to demonstration of efficacy of exogenous gene delivery. An alternative approach Is to repair the patient's own gene, and two innovative small molecule approaches have emerged as front-line experimental therapeutics: stop codon read through, and exon skipping. Both approaches are In human clinical trials, and aim to coax dystrophin protein production from mutant genes. In the clinically severe dog model of DMD, the exon-skipping approach is the first therapeutic method that showed improvement of multiple functional outcomes. The proposed CORT is focusing on exon-skipping, the approach that holds promise for the majority of DMD patients. Exon skipping as a drug development program Is highly complex. Patients have different mutations, and drugs must be customized to groups of patients sharing overlapping deletions. Given the high cost of drug development, there is an emerging consensus that exon skipping should achieve drug approval 'as a class'. Three exon-specific drugs should be systematically studied, showing safety and efficacy. The procedures and rules optimized for these three drugs can then be generalized to other, less commonly applicable exon- specific drugs, with reduced regulatory hurdles. The goal of this CORT is to systematically study the three most commonly applicable exon-specific drugs (exons 45,51.53). Project 1 will determine the splicing fidelity and protein function corresponding to the In-frame transcripts generated by the drugs. Project 2 will optimize sequence selection for each exon using multiple experimental systems, and test optimized drugs in a 1 yr pre-clinical efficacy study. Project 3 will carry out the first natural history study of the targeted in-frame deletions (Becker muscular dystrophy); this will permit some prediction of clinical efficacy from production of the relevant semi-functional dystrophin proteins. These three Projects draw upon two research cores: Core B (In vitro and In vivo functional assays), and Core C (Molecular diagnostics and cell banking).

描述（由申请人提供）：在1980年代后期，识别Duchenne肌肉营养不良基因和蛋白质的鉴定导致人们对快速转化为理性治疗剂的希望很高。通过基因疗法和干细胞疗法将新功能基因传递给小鼠模型肌肉的早期报道助长了这一希望。但是，这些相同的研究阐明了面临人类应用的非常高的障碍。治疗材料不足（细胞，病毒载体），全身传递中的挑战和免疫障碍都是表现出外源基因递送功效的障碍。另一种方法是修复患者自己的基因，两种创新的小分子方法已作为前线实验疗法出现：停止密码子读取和外显子跳过。两种方法都在人类的临床试验中，旨在哄骗突变基因产生肌营养不良蛋白的蛋白质。在DMD的临床严重狗模型中，外显子剥皮方法是第一种治疗方法，显示出多种功能结果的改善。拟议中的Cort专注于外显子鞋，这种方法对大多数DMD患者持希望。作为药物开发计划的外显子跳过非常复杂。患者有不同的突变，必须对具有重叠缺失的患者组定制药物。鉴于药物开发的高昂成本，有一个新兴的共识，即外显子跳过应“作为班级”获得药物认可。应系统地研究三种外显子特异性药物，显示安全性和有效性。然后，针对这三种药物进行优化的程序和规则可以推广到其他不常见的外部药物，并减少了监管障碍。该科特的目的是系统地研究三种最常用的外显子特异性药物（外显子45,51.53）。项目1将确定与药物产生的框内转录本相对应的剪接保真度和蛋白质功能。项目2将使用多个实验系统优化每个外显子的序列选择，并在1年临床前疗效研究中测试优化的药物。项目3将对有针对性的框架缺失（Becker肌肉营养不良）进行首次自然史研究；这将允许通过产生相关半功能性营养不良蛋白的产生来预测临床功效。这三个项目借鉴了两个研究核心：核心B（体外和体内功能测定）和核心C（分子诊断和细胞库）。