Genetic modification of aging and diseased striated muscle

描述(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病之一。DMD/BMD是由dystrophin基因突变引起的，以进行性肌肉萎缩为特征。BMD发病较晚，进展较慢，许多患者活得很好，超过中年。呼吸支持的改善也帮助许多DMD患者活到了第四个十年，两组患者最终都表现出肌肉质量的严重损失，取而代之的是纤维组织和脂肪组织。这些和其他肌肉萎缩疾病的基因治疗将通过允许将基因有效地转移到成年和老年患者的肌肉中的方法来促进，然而到目前为止，几乎所有的基因转移研究都集中在幼鼠身上。这个项目探索将治疗性基因输送到衰老小鼠肌肉的能力，重点是肌肉营养不良和衰老之间的相互作用。由于许多肌肉萎缩疾病通常表现在老年人身上，因此重要的是要关注与年龄相关的现象，这些现象抑制或以其他方式影响改善目标肌肉的生理状态的能力。对老年动物的肌肉进行基因改造的能力将有助于使用类似的方法来治疗其他肌肉损耗疾病，如衰老过程中的肌肉损失(石棺减少症)和与癌症相关的肌肉萎缩(恶病质)。我们的主要关注点将是衰老的正常小鼠和MDX小鼠，这是一种DMD/BMD模型。我们将评估通过系统递送腺相关病毒(AAV)载体来靶向成年和老年小鼠肌肉的能力，并将识别和绕过老年动物的基因递送障碍。我们将使用这些优化的方法来产生新的小鼠模型和方法，用于研究因高龄而加剧或与之相关的疾病和表型。最后，我们将开发改变老年动物肌肉结构和功能的方法，重点放在老年WT和营养不良小鼠身上，方法是联合传递改良的微型肌营养不良蛋白和肌肉质量调节剂。公共卫生相关性：这项工作与开发基于遗传的肌肉营养不良治疗方法高度相关，肌肉营养不良是影响年轻人、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，以减缓或阻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.