THERAPY NANOPARTICLES FOR MODULATION OF INFLAMMATION IN NEUROMUSCULAR DISEASE

描述（由申请人提供）：尽管通过基因和干细胞疗法治疗肌肉萎缩症已经显示出巨大的希望，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死亡的进展需要实际的替代策略。本提案的目的是基于我们实验室的最新进展，开发和评估肌肉萎缩症的多重治疗新方法，这些新方法可能会将靶向纳米系统用于肌肉萎缩症的诊断、治疗和基于图像的管理。在这个转化方案中，我们可以使用所有必要的合成和分析工具来最终确定目标纳米技术平台是否为肌肉萎缩症实验模型的管理增加了价值，这是一个迄今为止从未被测试过的命题。该提案的首要假设是：基于纳米技术的方法为神经肌肉疾病的诊断和治疗宝库增加了独特和有价值的资产，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。具体目标和实验计划中概述的可交付成果或结果如下：1)制备靶向疾病炎症生物标志物的纳米颗粒，通过基于图像的读取对导致心脏和骨骼肌恶化的早期炎症变化具有病理生理意义的选定分子生物标志物，无创、敏感、准确地报告肌营养不良疾病过程的活动和演变；2)开发新方法，将强效药物和遗传物质重复递送到炎症的靶向部位，与目前的治疗方法相比，毒性谱降低；3)将基于图像的疾病活动读数与治疗递送相结合，以便合理调整药物和剂量，并建立临床随访策略，以促进“个体化”临床管理。

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.