Myocardial Infarction Therapeutics

描述（由申请人提供）：心肌梗死（MI）是发达国家（包括美国）的主要死亡原因。每年有超过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。这些研究的目的是推进一种新的治疗方法，以MI伤口愈合，这是既显着有效，完全相反的传统智慧，以帮助70%的MI受害者到达医院。在鼠模型中，心肌梗死伤口愈合期间暂时性消耗树突状细胞（DC）可使心脏功能改善49%，心肌梗死面积减小65%。心脏功能是心肌梗死后生存的最大决定因素，对生活质量也有显著影响。这个项目的目标是开始将这一开创性的发现发展成为人类的治疗方法。待评价的药物是设计用于消耗MI后DC的抗体-毒素缀合物。它们对MI伤口愈合的观察效果值得注意，至少有两个原因。首先，免疫学家和心脏病学家传统上认为，通过MI后DC的消耗来干扰伤口愈合将导致灾难：即，弱化的组织（心脏破裂）和没有新的脉管系统。但情况并非如此。其次，DC耗竭的有益效果是惊人的（心脏功能改善49%）。在第一阶段，我们将研究两种在其DC上表达人受体（DEC 205和甘露糖）的转基因小鼠模型，以确定两种人mAb缀合物的安全性和有效性，这两种人mAb缀合物包含我们的主要治疗候选物。目标1。是确定这些药物在鼠模型中的功效。目标2.是测量目标1中确定的先导候选药物的毒性、分布和消除。一种暂时耗尽DC的治疗方法无异于一种范式转变。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。公共卫生相关性：心脏病发作是发达国家的主要死亡原因。通过暂时耗尽通常与炎症和免疫反应相关的细胞类型，我们已经能够在小鼠心脏病发作后显着改善心脏功能。该项目的总体目标是将这些结果推向一种帮助人类的药物。

DESCRIPTION (provided by applicant): Myocardial infarction (MI) is the leading cause of death in the developed world, including the United States. Each year over 8.1 million Americans have an MI; 30% die before reaching hospital and 10% die after hospitalization. The goal of these studies is to advance a novel therapeutic approach to MI wound healing that is both strikingly effective and exactly contrary to conventional wisdom in order to help the 70% of MI victims that reach hospital. Temporary depletion of dendritic cells (DC) during MI wound healing results in a 49% improvement in cardiac function and a 65% reduction in MI size in a murine model. Cardiac function is the greatest determinant of survival post-MI, and also has a significant effect on quality of life. The goal of this project is to begin to develop this seminal discovery into a therapy for humans. The drugs to be evaluated are antibody-toxin conjugates designed to deplete DC post-MI. Their observed effect on MI wound healing is noteworthy for at least two reasons. First, immunologists and cardiologists have conventionally thought that interfering with wound healing through the depletion of DC post-MI would result in catastrophe: i.e. weakened tissues (cardiac rupture) and no new vasculature. This has not been the case. Second, the beneficial effect of DC depletion is startling in its magnitude (49% improvement in heart function). In Phase I, we will study two transgenic mouse models which express human receptors (DEC 205 and mannose) on their DC to determine safety and efficacy of the two the human mAb conjugates which comprise our lead therapeutic candidates. Aim 1. is to determine efficacy of these drugs in the murine models. Aim 2. is to measure the toxicity, distribution and elimination of lead drug candidate identified in Aim 1. A treatment that temporarily depletes DC is nothing short of a paradigm shift. 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.