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: 8090706
• 负责人: ERIC P. HOFFMAN
• 金额: $ 167.44万
• 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/8090706
• 关键词: Center; Research; Translation; Systemic; Exon

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）： 20 世纪 80 年代末杜氏肌营养不良症基因和蛋白质的鉴定给人们带来了快速转化为合理治疗的厚望。通过基因疗法和干细胞疗法向小鼠模型肌肉传递新功能基因的早期报道点燃了这一希望。然而，这些研究也揭示了人类应用面临的非常高的障碍。治疗材料（细胞、病毒载体）不足、全身递送的挑战和免疫障碍仍然是证明外源基因递送功效的障碍。另一种方法是修复患者自身的基因，两种创新的小分子方法已成为一线实验疗法：终止密码子通读和外显子跳跃。这两种方法都在人体临床试验中，旨在诱导突变基因产生肌营养不良蛋白。在临床严重的 DMD 狗模型中，外显子跳跃方法是第一个显示出多种功能结果改善的治疗方法。拟议的 CORT 重点关注外显子跳跃，这种方法为大多数 DMD 患者带来了希望。外显子跳跃作为药物开发项目非常复杂。患者具有不同的突变，必须针对具有重叠缺失的患者群体定制药物。鉴于药物开发成本高昂，人们逐渐达成共识，即外显子跳跃应该“作为一类”获得药物批准。应该系统地研究三种外显子特异性药物，以显示安全性和有效性。针对这三种药物优化的程序和规则可以推广到其他不太常用的外显子特异性药物，同时减少监管障碍。该CORT的目标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 将确定与药物生成的框内转录物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，并在为期1年的临床前疗效研究中测试优化的药物。项目3将开展首次针对框内靶向缺失（贝克尔肌营养不良症）的自然历史研究；这将允许通过相关半功能性肌营养不良蛋白的产生来预测临床疗效。这三个项目利用两个研究核心：核心 B（体外和体内功能测定）和核心 C（分子诊断和细胞库）。