Therapy Nanoparticles for Modulation of Inflammation in Neuromuscular Disease

描述(申请人提供)：尽管基因和干细胞疗法在肌营养不良症的治疗方面显示出巨大的前景，类固醇似乎可以改善生理功能，但这些患者整个疾病过程的复杂性和死亡的快速进展要求实用的替代策略。本建议的目的是基于我们实验室的最新进展，开发和评估肌营养不良症的多元化治疗的新方法，这些方法可能会将靶向纳米系统应用于肌营养不良症的诊断、治疗和基于图像的管理。在这份翻译提案中，我们可以使用所有必要的合成和分析工具来最终确定一个有针对性的纳米技术平台是否为肌肉营养不良的实验模型的管理增加了价值，这是一个迄今为止从未经过测试的命题。这一提议的主要假设是：基于纳米技术的方法为神经肌肉疾病的诊断和治疗增加了独特和宝贵的资产，并将以直接转化的方式为神经肌肉疾病的临床管理做出贡献。在特定目标中设想并在实验计划中概述的可交付成果或结果是：1)针对疾病的炎症生物标记物的纳米颗粒的配方，以非侵入性、灵敏和准确的方式，通过基于图像的读数，选择对导致心肌和骨骼肌恶化的早期炎症变化具有病理生理学意义的分子生物标记物，来非侵入性、灵敏、准确地报告肌营养不良疾病过程的活动和演变；2)开发新的方法，以与当前的治疗方法相比，将有效的药物和遗传物质重复输送到炎症的靶部位，并降低毒性；3)将基于图像的疾病活动读数与治疗提供相结合，以允许合理调整药剂和剂量，并建立临床随访策略，以促进“个体化”的临床管理。 与公共卫生相关：尽管基因和干细胞疗法在肌营养不良症的治疗方面显示出巨大的前景，类固醇似乎可以改善生理功能，但这些患者整个疾病过程的复杂性和死亡的快速进展要求实用的替代策略。本建议的目的是基于我们实验室的最新进展，开发和评估肌营养不良症的多元化治疗的新方法，这些方法可能会将靶向纳米系统应用于肌营养不良症的诊断、治疗和基于图像的管理。在这份翻译提案中，我们可以使用所有必要的合成和分析工具来最终确定一个有针对性的纳米技术平台是否为肌肉营养不良的实验模型的管理增加了价值，这是一个迄今为止从未经过测试的命题。

DESCRIPTION (provided by applicant): Although great promise has been shown for therapy of muscular dystrophy by gene and stem cell therapies, and steroids appear to improve physiological function, the complexity of the total disease process and the rapid progression to death in these patients begs for practical alternative strategies. The purpose of this proposal is to develop and evaluate new approaches to multiplexed therapeutics of muscular dystrophy based on recent progress in our laboratory that may bring targeted nanosystems to bear on diagnosis, therapy, and image-based management of muscular dystrophy. In this translational proposal, all of the required synthetic and analytical tools are at our disposal to conclusively determine if a targeted nanotechnology platform adds value to the management of experimental models of muscular dystrophy, which is a proposition that heretofore has never been tested. The overarching hypothesis of this proposal is that: nanotechnology-based approaches add unique and valuable assets to the diagnostic and therapeutic armamentarium in neuromuscular disorders, and will contribute in a directly translational way to the clinical management of neuromuscular disorders. The deliverables, or outcomes, envisioned in the specific aims and outlined in the experimental plan are: 1) Formulation of nanoparticles targeted to inflammatory biomarkers of disease to noninvasively, sensitively, and accurately report the activity and the evolution of the muscular dystrophy disease process through image- based readouts of selected molecular biomarkers of pathophysiological significance to the early inflammatory changes that contribute to the deterioration of cardiac and skeletal muscle; 2) Development of novel methods for repeated delivery of potent drugs and genetic materials to targeted sites of inflammation with reduced toxicity profiles as compared with current therapeutic approaches; and 3) Integration of image-based readouts of disease activity in conjunction with therapeutic delivery to allow rational adjustment of agents and dosing, and establishment of clinical follow-up strategies to facilitate "individualized" clinical management. PUBLIC HEALTH RELEVANCE: Although great promise has been shown for therapy of muscular dystrophy by gene and stem cell therapies, and steroids appear to improve physiological function, the complexity of the total disease process and the rapid progression to death in these patients begs for practical alternative strategies. The purpose of this proposal is to develop and evaluate new approaches to multiplexed therapeutics of muscular dystrophy based on recent progress in our laboratory that may bring targeted nanosystems to bear on diagnosis, therapy, and image- based management of muscular dystrophy. In this translational proposal, all of the required synthetic and analytical tools are at our disposal to conclusively determine if a targeted nanotechnology platform adds value to the management of experimental models of muscular dystrophy, which is a proposition that heretofore has never been tested.