Depletion of Dendritic Cells by Immunotoxin as Therapy for Myocardial Infarction

描述（由申请人提供）：MI是发达国家（包括美国）的主要死因。2005年，超过810万美国人患有MI; 30%在到达医院之前死亡，10%在住院后死亡。我们相信我们可以帮助的是70%的住院患者-仅在美国就有100万人的生命处于平衡状态，并改善了数百万人的生活质量。这些研究的目标是为临床带来心肌梗死（MI）和缺血再灌注（IR）伤口愈合的新型治疗方法。这种方法既非常有效，又与传统智慧完全相反。在小鼠模型中，我们已经表明，在MI伤口愈合期间暂时耗尽树突状细胞（DC）导致心脏功能改善80%和MI大小减小65%。心脏功能是心肌梗死后生存率的最大决定因素。我们将通过在我们专有的转基因（TG）小鼠模型中完成临床前小鼠安全性和有效性测试，继续将这一开创性发现开发为人类治疗。该产品是一种人甘露糖受体（hMR）靶向融合蛋白，旨在消耗MI后的DC。DC在MI伤口愈合中的先前未被认识的作用值得注意，至少有两个原因。首先，免疫学家和心脏病学家传统上认为MI后DC的耗尽将导致灾难：即弱化的组织（心脏破裂）和没有新的脉管系统。其次，DC耗竭的有益效果在其幅度上是惊人的（与对照相比，心脏功能改善高达80%）。一种暂时耗尽DC的治疗方法无异于一种范式转变，我们相信这将导致死亡率的大幅降低和患者生活的深刻改善。在I期，我们在高度人相关的鼠模型中证明了hMR靶向免疫毒素的安全性和有效性。在第二阶段，我们将通过严格的剂量优化以及在小鼠模型和人体组织学和血液工作（体外）中的安全性和有效性研究完成临床前试验。令人信服的安全性和有效性结果加上缺乏合适的第二种属意味着本文所述的工作预计足以成功申请IND。我们正在与临床医生和FDA就这一临床前途径进行持续讨论 作为I期临床试验的设计。我们将与战略合作伙伴合作，将药物推向市场。初步结果表明，这一战略可能会导致死亡率急剧下降，并在MI受害者的生活中的深刻改善。

DESCRIPTION (provided by applicant): MI is the leading cause of death in the developed world, including the United States. In 2005 over 8.1 million Americans had an MI; 30% died before reaching hospital and 10% died after hospitalization. It is the 70% who reach hospital that we believe we can help - a million lives in the balance and an improved quality of life for millions more - in the US alone. The goal of these studies is to bring a novel therapeutic approach to myocardial infarction (MI) and ischemia-reperfusion (IR) wound healing to the clinic. The approach is both strikingly effective and exactly contrary to conventional wisdom. In a murine model we have shown that temporary depletion of dendritic cells (DC) during MI wound healing results in an 80% improvement in cardiac function and a 65% reduction in MI size. Cardiac function is the greatest determinant of survival post-MI. We will continue the development of this seminal discovery into a human therapy by completing preclinical murine safety and efficacy testing in our proprietary transgenic (TG) mouse model. The product is a human mannose receptor (hMR) targeted fusion protein designed to deplete DC post-MI. The previously unrecognized role for DC in MI wound healing is noteworthy for at least two reasons. First, immunologists and cardiologists have conventionally thought that depletion of DC post-MI would result in catastrophe: i.e. weakened tissues (cardiac rupture) and no new vasculature. Second, the beneficial effect of DC depletion is startling in its magnitude (up to 80% improvement in heart function vs. controls). A treatment that temporarily depletes DC is nothing short of a paradigm shift that we believe will lead to a sharp reduction in mortality and profound improvements in the lives of patients. In Phase I, we demonstrated safety and efficacy of a hMR-targeted immunotoxin in a highly human- relevant murine model. In Phase II we will complete pre-clinical testing through rigorous dose optimization as well as safety and efficacy studies in murine models and human histology and blood work (in vitro). The compelling safety and efficacy results combined with the lack of a suitable second species means the work described herein is expected to be sufficient for a successful IND application. We are engaged in continuing discussions with both clinicians and the FDA regarding this pre-clinical path as well as the design of a Phase I clinical trial. We will bring the drug to market in collaboration with or strategic partners. Initial results suggest that this strategy may lead to a sharp reduction in mortality and profound improvements in the lives of victims of MI.