THERAPY NANOPARTICLES FOR MODULATION OF INFLAMMATION IN NEUROMUSCULAR DISEASE

描述（由申请人提供）：虽然通过基因和干细胞疗法治疗肌营养不良症已经显示出很大的前景，并且类固醇似乎可以改善生理功能，但这些患者的整个疾病过程的复杂性和快速进展至死亡需要实际的替代策略。该提案的目的是根据我们实验室的最新进展开发和评估肌营养不良症多重治疗的新方法，这些新方法可能会使靶向纳米系统对肌营养不良症的诊断，治疗和基于图像的管理产生影响。在这个转化的建议中，所有需要的合成和分析工具都在我们的处置中，以最终确定是否有针对性的纳米技术平台增加了肌肉萎缩症实验模型的管理价值，这是一个迄今为止从未被测试过的命题。 该提案的总体假设是：基于纳米技术的方法为神经肌肉疾病的诊断和治疗设备增加了独特和有价值的资产，并将以直接转化的方式促进神经肌肉疾病的临床管理。在具体目标中设想并在实验计划中概述的可交付成果或成果是：1）靶向疾病的炎性生物标志物的纳米颗粒的制剂，通过图像准确报道肌营养不良症病程的活动和演变，基于选定的分子生物标志物的病理生理学意义的早期炎症变化，有助于心脏的恶化，和骨骼肌; 2）开发新的方法，用于将有效药物和遗传物质重复递送到炎症的靶向部位，与当前的治疗方法相比，具有降低的毒性特征;以及3）将疾病活动的基于图像的读数与治疗递送相结合，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”临床管理。 公共卫生相关性：虽然通过基因和干细胞疗法治疗肌营养不良症已经显示出巨大的前景，并且类固醇似乎可以改善生理功能，但这些患者的总疾病过程的复杂性和快速进展至死亡要求实际的替代策略。本提案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多重治疗的新方法，这些新方法可能会使靶向纳米系统对肌营养不良症的诊断，治疗和基于图像的管理产生影响。在这个转化的建议中，所有需要的合成和分析工具都在我们的处置中，以最终确定是否有针对性的纳米技术平台增加了肌肉萎缩症实验模型的管理价值，这是一个迄今为止从未被测试过的命题。

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.