Delivery of superoxide dismutase to the myocardium for regeneration with polyketa

描述（由申请人提供）：心衰的主要原因是心肌梗死后的局部心肌丧失。由于组织的损失是高度局部的，并且内源性反应不足以修复，最近的努力集中在使用各种治疗方案来替换丢失的细胞。梗死后超氧化物的产生对成体肌细胞和局部干细胞群的细胞死亡有重要作用。虽然直接注射蛋白质可能会有一些好处，但快速扩散和半衰期短限制了它们在临床上的应用。该建议的目的是将超氧化物歧化酶（SOD）包裹在聚酮颗粒中，以增强心肌保留并改善梗死后的功能。基因治疗和基因敲除小鼠研究表明，SOD具有治疗心肌梗死后心功能障碍的明显潜力；然而，该蛋白的半衰期短限制了其临床应用。聚酮颗粒是一类稳定的新型聚合物，可降解为FDA批准的化合物，易于修饰，可以在保持活性的同时包裹蛋白质。该建议的中心假设是，聚酮颗粒可用于以可量化的方式递送超氧化物歧化酶，以减少心肌梗死后超氧化物的产生。这种减少将导致成体肌细胞的细胞死亡减少，并保留局部干细胞群。此外，本提案还将验证聚酮类化合物中的SOD可以作为辅助治疗来提高细胞治疗效果的假设。这项R21提案的成功完成将证明负载SOD的聚酮颗粒可用于治疗心肌梗死后的心功能障碍。此外，聚酮具有封装小分子抑制剂、DNA和蛋白质的能力。考虑到心肌梗死后复杂的内源性反应，我们相信这一提议的数据将引起广泛的兴趣，使用聚酮用于心肌给药。

DESCRIPTION (provided by applicant): The major cause of heart failure is the regional loss of myocardium following myocardial infarction. Because the loss of tissue is highly localized, and the endogenous response is not sufficient for repair, recent efforts have focused on replacement of the lost cells using a variety of treatment options. Superoxide production following infarction contributes significantly to cell death of the adult myocytes and local stem cell populations. While direct injection of proteins may give some benefit, rapid diffusion and short half-lives limit their use clinically. The objective of this proposal is to encapsulate superoxide dismutase (SOD), a powerful endogenous scavenger of superoxide, within polyketal particles to enhance myocardial retention and improve function following infarction. Gene therapy and knockout mouse studies demonstrate a clear potential of SOD to treat cardiac dysfunction following myocardial infarction; however, the short half-life of the protein has limited its use clinically. Polyketal particles are a new class of polymers that are stable, degrade in to FDA- approved compounds, can be modified easily and can encapsulate proteins while retaining activity. The central hypothesis of this proposal is that polyketal particles can be used to deliver SOD in a quantifiable manner to reduce superoxide production following myocardial infarction. This reduction will lead to decreased cell death of adult myocytes, as well as preserve the local stem cell populations. In addition, this proposal will also test the hypothesis that SOD within polyketals can serve as an adjunct treatment to improve the efficacy of cell therapy. The successful completion of this R21 proposal will demonstrate that polyketal particles loaded with SOD can be used to treat cardiac dysfunction following myocardial infarction. Furthermore, polyketals have the ability to encapsulate small molecule inhibitors, DNA and proteins. Given the complicated endogenous response following myocardial infarction, we believe that data from this proposal will generate widespread interest in using polyketals for myocardial drug delivery. NARRATIVE: Congestive heart failure is a leading cause of morbidity and mortality worldwide and effective treatment options are greatly needed. We propose to encapsulate and deliver superoxide dismutase, an unstable antioxidant with therapeutic potential, directly to the myocardium using a new class of polymers called polyketals. This proposal will demonstrate that polyketals containing antioxidant proteins can be used to help regenerate cardiac tissue following myocardial infarction.