Dystrophin and Heart Disease

肌营养不良蛋白和心脏病

基本信息

批准号：
9367436
负责人：
JOSEPH Mark METZGER
金额：
$ 38.08万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9367436
关键词：
Animal Model Attention Benchmarking Biochemical Cardiac Cardiac health Cardiomyopathies Cause of Death Clinical Clinical Trials Complex Cytoskeletal Proteins Cytoskeleton Data Disease Dissection Duchenne muscular dystrophy Dystrophin Effectiveness Exons Extracellular Matrix Future Genes Genetic Glycoproteins Half-Life Health Heart Heart Diseases Heart failure Inherited Knowledge Lead Length Link LoxP-flanked allele Membrane Methods Mission Muscle Myocardium Patients Peptides Performance Physiological Proteins Role Somatic Cell Stress Striated Muscles Structure Structure-Activity Relationship Technology Testing Therapeutic Time Titrations Transgenic Mice Translating United States National Institutes of Health Work base clinical efficacy clinically relevant comparative design effective therapy exon skipping gene therapy genetic technology heart function in vivo micro-dystrophin mortality protein complex public health relevance spatiotemporal success

项目摘要

Abstract Significant health relevance of this application is evident in our mechanistic dissection of the role of the cytoskeletal protein dystrophin in heart health and disease. Numerous inherited and acquired cardiac diseases are caused by deficits in dystrophin, including, notably, Duchenne muscular dystrophy (DMD), in which there is the complete loss of the dystrophin protein. Dystrophin is a 427 kDa cytoskeletal protein and is a vital link between the cytoskeleton, the muscle membrane and the extracellular matrix. Heart disease accounts for a significant mortality in DMD, for which there is no cure or long-term effective treatment. Recent advances in genetic technologies have fueled enthusiasm for gene-based therapeutic restitution of truncated dystrophins as a treatment for DMD. For DMD patients, several exon skipping clinical trial studies are ongoing and proof-of- concept somatic cell gene editing studies provide evidence of effectiveness in animal models. To date, none of these efforts have successfully translated to clinical efficacy in DMD patients. We posit reduced in vivo stability of internally truncated dystrophins is a significant barrier to ultimate clinical efficacy. We provide preliminary evidence that truncated dystrophins can be highly unstable in vivo, with markedly faster turnover rates than full length dystrophin. Reduced stability of a truncated dystrophin is expected to have significant implications for long-term clinical success by negatively impacting duration of therapeutic action in vivo. Further, the therapeutic expression threshold to confer significant cardio-protection with truncated dystrophin molecules is not known and truncated dystrophin proteins can confer only partial physiological restitution in dystrophin-deficient hearts in vivo. We have established a proof-of-concept approach to directly determine the stability and physiological expression threshold for truncated dystrophins in the heart in vivo. Guiding hypothesis: Clinically-designed gene therapy, gene-edited or exon skipped truncated dystrophin molecules will have significantly shorter half-lives in the heart in vivo, compared to intact full length dystrophin, compromising duration of action effects. The Specific Aims are to establish the in vivo stability/half-life of clinically relevant truncated dystrophins in the dystrophic heart. This knowledge is essential for the success of gene-based clinical trials for DMD. These studies will have a lasting impact on the field by illuminating the key dystrophin structure-function benchmarks required for long- term effectiveness of current and future gene-based therapies for DMD patients.

抽象的我们对本应用的重要健康相关性在我们对心脏健康和疾病中的细胞骨架蛋白肌病。许多继承和获得的心脏病是由肌营养不良蛋白的缺陷引起的，包括duchenne肌肉营养不良（DMD），其中存在肌营养不良蛋白的完全丧失。肌营养不良蛋白是427 kDa细胞骨架蛋白，是一个重要的联系在细胞骨架，肌肉膜和细胞外基质之间。心脏病占 DMD的显着死亡率，没有治愈或长期有效治疗。最近的进步遗传技术激发了基于基因基因的治疗性肌营养不良蛋白的治疗恢复的热情 DMD的处理。对于DMD患者，持续进行了几项外显子跳过临床试验研究，并且证明概念体细胞基因编辑研究提供了动物模型中有效性的证据。迄今为止，没有这些努力已成功地转化为DMD患者的临床功效。我们认为体内稳定性降低内部截短的肌营养不良蛋白是最终临床功效的重要障碍。我们提供初步证据表明截短的肌营养不良蛋白在体内可能是高度不稳定的，其周转率明显比满长度肌营养不良蛋白。预计截短的肌营养不良蛋白的稳定性降低对长期临床成功，通过负面影响体内治疗作用的持续时间。此外，治疗性表达阈值允许用截短的肌营养不良蛋白分子赋予明显的心脏保护截短的肌营养不良蛋白可以仅在肌营养不良的心脏中赋予部分生理恢复原状体内。我们已经建立了一种概念验证方法，可以直接确定稳定性和生理体内心脏中截短肌营养不良蛋白的表达阈值。指导假设：临床设计的基因治疗，基因编辑或外显子跳过截短的肌营养不良蛋白分子的半衰期将明显较短与完整的全长肌营养不良蛋白相比，心脏在体内损害了作用效果。具体目的是建立营养不良的临床相关截短肌营养不良蛋白的体内稳定性/半衰期心。这种知识对于基于基因的DMD临床试验的成功至关重要。这些研究将有通过阐明长期需要的关键肌营养不良蛋白结构功能基准，对现场产生持久影响 DMD患者的当前和未来基于基因的疗法的期限有效性。