Integrated Strategies for Novel Treatment of Myocardial Ischemia

描述（由申请人提供）：冠状动脉疾病（CAD）是美国发病率和死亡率的头号原因。尽管医学治疗取得了进展，但一些患者继续出现难治性症状，需要采取更积极的措施，如左心室辅助装置（LVAD）或原位心脏移植（OHT）。在过去的十年中，重组DNA技术的显着进步使得CAD的分子和细胞治疗的发展成为可能。特别是心脏基因治疗领域已经从体外研究发展到临床前试验再到多中心试验。然而，最近的II/III期试验已经发现了一些问题，例如难以控制腺病毒载体的免疫原性、靶向表达至心脏组织以及递送后重组基因的体内监测。因此，开发安全且可产生靶向组织递送的新型非病毒载体将是一个重大进展。另一个重大进展将是非侵入性技术的发展，以评估基因表达，为整个研究领域提供新的催化剂。该提案的目的是（1）开发非免疫原性“小环”DNA载体，其将显著提高心脏中的转染效率，（2）使用遗传和分子测定的综合策略理解基于基因的治疗的机制，以及（3）评估临床前大型动物模型中的安全性和有效性。在5年结束时，我们希望将来将这些发现转化为基于微环的基因治疗对CAD患者的治疗。

DESCRIPTION (provided by applicant): Coronary artery disease (CAD) is the number one cause of morbidity and mortality in the United States. Despite advances in medical therapies, some patients continue to develop refractory symptoms requiring more aggressive measures such as left ventricular assist device (LVAD) or orthotopic heart transplantation (OHT). Over the past decade, remarkable progress in recombinant DNA technology has enabled the development of molecular and cellular treatments for CAD. In particular, the field of cardiac gene therapy has evolved from in vitro studies to pre-clinical testing to multi-center trials. However, recent phase II/III trials have uncovered problems such as difficulties in controlling immunogenicity of adenoviral vectors, targeting expression to cardiac tissues, and in vivo monitoring of recombinant genes post delivery. Thus, the development of novel non-viral vectors that are safe and can yield targeted tissue delivery would be a major advance. Another significant advance will be the development of noninvasive techniques to assess gene expression, providing a new catalyst for the entire field of investigation. The aims of this proposal are to (1) develop non- immunogenic "minicircle" DNA vectors will significantly improve transfection efficiency in the heart, (2) understand the mechanisms of gene based therapy using integrated strategies of genetic and molecular assays, and (3) to evaluate the safety and efficacy in pre-clinical large animal models. At the end of 5 years, we hope to translate these findings to treatment of CAD patients with minicircle- based gene therapy in the future.