Depletion of Dendritic Cells by Immunotoxin as Therapy for Myocardial Infarction

描述（由申请人提供）：心肌梗死是包括美国在内的发达国家的主要死亡原因。2005年，超过810万美国人患有心肌梗死；30%在到达医院前死亡，10%在住院后死亡。仅在美国，我们相信我们可以帮助到70%去医院的人——100万人的生命处于平衡状态，数百万人的生活质量得到改善。这些研究的目的是为临床治疗心肌梗死（MI）和缺血再灌注（IR）伤口愈合提供一种新的治疗方法。这种方法既非常有效，又与传统观念完全相反。在小鼠模型中，我们已经表明，在心肌梗死伤口愈合过程中，树突状细胞（DC）的暂时消耗导致心功能改善80%，心肌梗死大小减少65%。心功能是心肌梗死后生存的最大决定因素。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发展为人类疗法。该产品是一种针对人甘露糖受体（hMR）的融合蛋白，旨在消除心肌梗死后的DC。以前未被认识到的DC在心肌梗死伤口愈合中的作用值得注意，至少有两个原因。首先，免疫学家和心脏病学家传统上认为心肌梗死后DC的消耗会导致灾难：即组织减弱（心脏破裂）和没有新的血管系统。其次，DC消耗的有益效果是惊人的（与对照组相比，心脏功能改善高达80%）。一种暂时消耗DC的治疗方法是一种范式的转变，我们相信这将导致死亡率的急剧降低，并深刻改善患者的生活。在第一阶段，我们在一个高度人类相关的小鼠模型中证明了一种hmr靶向免疫毒素的安全性和有效性。在II期，我们将通过严格的剂量优化以及小鼠模型和人类组织学和血液工作（体外）的安全性和有效性研究完成临床前测试。令人信服的安全性和有效性结果加上缺乏合适的第二种，意味着本文所述的工作预计足以成功地进行IND申请。我们正在继续与临床医生和FDA就这一临床前途径进行讨论

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. PUBLIC HEALTH RELEVANCE: Heart attacks are the leading cause of death in the developed world. By temporarily depleting a cell type commonly associated with inflammatory and immune responses, we have been able to dramatically improve heart function after a heart attack in mice. The overall goal of this project is to advance these results toward a drug that will help humans.