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主要死亡原因。每年超过810万美国人有MI；到达医院前30％死亡，住院后10％死亡。这些研究的目的是推进一种新型的治疗方法，用于MI伤口愈合，这既有效，又与传统智慧完全相反，以帮助70％的MI受害者到达医院。在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提高49％，而在鼠模型中，MI大小减少了65％。心脏功能是MI生存后最大的决定因素，并且对生活质量也有重大影响。该项目的目的是开始将这种开创​​性发现发展为对人类的疗法。要评估的药物是抗体毒素结合物，旨在消耗DC后DC。他们观察到的对MI伤口愈合的影响至少有两个原因值得注意。首先，免疫学家和心脏病学家通常认为，通过DC MI的耗竭来干扰伤口愈合会导致灾难：即弱组织（心脏破裂），没有新的脉管系统。事实并非如此。其次，直流耗竭的有益作用在其大小上令人震惊（心脏功能提高了49％）。在第一阶段，我们将研究两种转基因小鼠模型，它们在其直流上表达人体受体（12月205日和甘露糖），以确定两个人类mAB偶联物的安全性和功效，包括我们的铅治疗候选者。目的1是确定这些药物在鼠模型中的功效。目的2是测量目标1中确定的铅药物候选药物的毒性，分布和消除。一种暂时耗尽DC的治疗方法无非是范式转移。最初的结果表明，这种策略可能会导致死亡率急剧下降，并在MI的受害者的生活中得到深远的改善。公共卫生相关性：心脏病发作是发达国家死亡的主要原因。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有助于人类的药物。