Myocardial Infarction Therapeutics

心肌梗塞治疗

• 批准号: 7747638
• 负责人: EBO DERK DE MUINCK
• 金额: $ 19.91万
• 依托单位: CELDARA MEDICAL, LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7747638
• 关键词: American; Animals; Antibodies; Blood; Cardiac; Cause of Death; Clinical Paths; Clinical assessments; Collaborations; Complex; DEC-205 receptor; Dendritic Cells; Dose; Drug Delivery Systems; Drug Labeling; Echocardiography; Equilibrium; Feces; Flow Cytometry; Goals; Histology; Hospitalization; Hospitals; Human; Human body; Immune response; Immunoglobulin Fragments; Immunohistochemistry; Immunologist; Immunotoxins; In Vitro; Inflammatory; Injection of therapeutic agent; Lead; Letters; Life; Link; Mannose; Marketing; Maximum Tolerated Dose; Measures; Modeling; Monitor; Mus; Myocardial Infarction; Myocardial rupture; Patients; Pharmaceutical Preparations; Phase; Pseudomonas aeruginosa toxA protein; Quality of life; Recovery of Function; Reperfusion Injury; Role; Safety; Seminal; Spleen; Testing; Theoretical model; Therapeutic; Tissues; Toxic effect; Toxin; Transgenic Mice; United States; Urine; Work; Wound Healing; base; cell type; combat; design; drug candidate; drug efficacy; effective therapy; heart function; improved; mannose receptor; morphometry; mortality; mouse model; myocardial infarct sizing; novel therapeutic intervention; pre-clinical; public health relevance; receptor

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.

描述（由申请人提供）：心肌梗塞（MI）是包括美国在内的发达国家的首要死因。每年有超过 810 万美国人患有心肌梗死； 30% 在到达医院之前死亡，10% 在住院后死亡。这些研究的目标是推进一种新颖的 MI 伤口愈合治疗方法，该方法不仅非常有效，而且完全违背传统观念，以帮助 70% 的 MI 受害者到达医院。在小鼠模型中，MI 伤口愈合过程中树突状细胞 (DC) 的暂时耗竭导致心脏功能改善 49%，MI 大小缩小 65%。心脏功能是心肌梗死后生存的最大决定因素，并且对生活质量也有显着影响。该项目的目标是开始将这一开创性的发现发展为人类的疗法。待评估的药物是抗体-毒素缀合物，旨在消耗心肌梗死后的 DC。观察到它们对 MI 伤口愈合的影响值得注意，至少有两个原因。首先，免疫学家和心脏病学家传统上认为，心肌梗死后通过消耗 DC 来干扰伤口愈合会导致灾难：即组织衰弱（心脏破裂）并且没有新的脉管系统。但事实并非如此。其次，DC 消耗的有益效果令人震惊（心脏功能改善 49%）。在第一阶段，我们将研究两种在 DC 上表达人类受体（DEC 205 和甘露糖）的转基因小鼠模型，以确定构成我们主要候选治疗药物的两种人类 mAb 缀合物的安全性和有效性。目的 1. 确定这些药物在小鼠模型中的功效。目标 2. 是测量目标 1 中确定的主要候选药物的毒性、分布和消除。暂时消耗 DC 的治疗无异于范式转变。初步结果表明，这一策略可能会大幅降低死亡率并显着改善心肌梗死受害者的生活。公共卫生相关性：心脏病是发达国家死亡的主要原因。通过暂时消除通常与炎症和免疫反应相关的细胞类型，我们能够显着改善小鼠心脏病发作后的心脏功能。该项目的总体目标是将这些结果推向一种可以帮助人类的药物。