Genetic modification of aging and diseased striated muscle

描述（由申请人提供）：Duchenne肌营养不良症（DMD）和等位基因Becker MD是最常见的人类遗传性疾病之一。DMD/BMD是由肌营养不良蛋白基因突变引起的，其特征是进行性肌肉萎缩。BMD显示较晚的发病和较慢的进展，许多患者生活在中年之后。改善的呼吸支持也有助于许多DMD患者活到40岁，这两组患者最终都表现出肌肉质量的严重损失，并被纤维化和脂肪组织所取代。这些和其他肌肉萎缩性疾病的基因治疗将通过允许有效的基因转移到成年和老年患者的肌肉的方法来促进，但迄今为止几乎所有的基因转移研究都集中在年轻的小鼠上。该项目探索了将治疗基因传递到衰老小鼠肌肉的能力，重点是肌肉萎缩症和衰老之间的相互作用。由于许多肌肉萎缩症通常在老年人中表现出来，因此重要的是关注抑制或以其他方式影响改善目标肌肉的生理状态的能力的年龄相关现象。对老年动物肌肉进行遗传修饰的能力将有助于使用类似的方法治疗其他肌肉萎缩性疾病，如衰老期间的肌肉损失（肌肉减少症）和与癌症相关的肌肉萎缩（恶病质）。我们的主要重点将是衰老的正常和mdx小鼠，DMD/BMD的模型。我们将评估通过腺相关病毒（AAV）载体的全身递送靶向成年和老年小鼠肌肉的能力，并将识别和规避老年动物中基因递送的障碍。我们将使用这些优化的方法来产生新的小鼠模型和方法，用于研究由高龄加重或与高龄相关的疾病和表型。最后，我们将开发在老年动物中修改肌肉结构和功能的方法，重点是通过共同递送改进的迷你肌营养不良蛋白和肌肉质量调节剂来改善老年WT和营养不良小鼠。 公共卫生相关性：这项工作与开发基于基因的肌营养不良症治疗方法高度相关，肌营养不良症是影响年轻人，成年人和老年人的常见遗传性疾病。这些相同的方法也应该广泛适用于开发干预措施，以减缓或停止与正常衰老相关的肌肉萎缩。

DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD) and the allelic Becker MD is one of the most common human genetic disorders. DMD/BMD is caused by mutations in the dystrophin gene, and is characterized by progressive muscle wasting. BMD displays a later onset and slower progression, with many patients living well past middle age. Improved respiratory support is also helping many DMD patients live into their fourth decade, and both groups ultimately display a profound loss of muscle mass that is replaced by fibrotic and adipose tissues. Genetic therapies for these and other muscle wasting disorders would be facilitated by methods that allow efficient gene transfer to muscles of adult and old patients, yet virtually all studies of gene transfer to date have focused on young mice. This project explores the ability to deliver therapeutic genes to muscles of aging mice, with a focus on the interplay between muscular dystrophy and aging. Since many muscle wasting disorders typically manifest in older individuals, it is important to focus on age related phenomena that inhibit or otherwise impact the ability to improve the physiological state of the target muscles. The ability to genetically modify muscles of old animals would facilitate the use of similar approaches for other muscle wasting disorders, such as muscle loss during aging (sarcopenia) and muscle atrophy associated with cancer (cachexia). Our primary focus will be on aging normal and mdx mice, a model for DMD/BMD. We will evaluate the ability to target muscles of adult and old mice by systemic delivery of adeno-associated viral (AAV) vectors and will identify and circumvent barriers to gene delivery in elderly animals. We will use these optimized methods to generate new mouse models and methods for studying disorders and phenotypes that are exacerbated by, or associated with, advanced age. Finally, we will develop methods to modify muscle structure and function in elderly animals, with a focus on old WT and dystrophic mice by co-delivery of improved mini-dystrophins and modulators of muscle mass. PUBLIC HEALTH RELEVANCE: This work is highly relevant to developing genetic-based treatments for the muscular dystrophies, which are common inherited disorders that affect young, adult and elderly individuals. These same methods should also be broadly applicable to developing interventions to slow or halt muscle wasting associated with normal aging.