Preclinical Consortium to Facilitate Translation of Cardioprotective Therapies

描述(由申请人提供)： 缺血性心脏病的原因--每年有60万人死亡(占所有死亡人数的20%)。据估计，每年有130万美国人患有心肌梗死；由于他们的预后取决于心肌梗死的大小，因此缩小心肌梗死面积对降低发病率和死亡率至关重要。30多年来，NHLBI在旨在开发心肌梗死保护疗法的临床前研究上投入了大量资源(至少数亿美元)，并声称已有数百种(如果不是数千种)疗法在临床前模型中限制心肌梗死范围。不幸的是，由于方法学上的问题，这项巨大的投资并没有产生任何值得注意的临床应用，目前也没有心脏保护疗法可供临床使用。经过30年徒劳无功的努力，需要一种新的方法来克服阻碍心脏保护疗法转化的问题。对临床前研究应用与临床试验相同的科学严谨标准的时候到了。利用NHLBI建立的临床试验网络作为开发研究共享的协作基础设施的模型，我们提出了一个临床前联盟，它将以类似于临床网络的方式运行。六个机构将合作进行盲法、随机化和充足动力的研究，使用严格的设计、完整的剂量-反应分析、最优的统计方法、独立的数据分析和统计核心、组织学、血浆生物标记物和相关动物模型(包括有意识的动物和共病模型)三个物种(小鼠、兔子、猪)。以确保重现性。每项研究将在两个中心使用相同的方案进行。这一独特的基础设施将使对前景看好的心脏保护疗法进行严格的临床前评估成为可能，并将为整个科学界(包括学术界和生物医学行业)提供服务，从而构成公共资源。将向整个科学界征求研究疗法的建议，并由一个独立的议定书审查委员会审查，该委员会将挑选将实施的建议。每年将至少测试3种疗法。该联合体结构将确保它将成为所有感兴趣的调查人员可利用的真正公共资源，并将以公平的方式对所有拟议的研究进行评价。30封信(附录)证明了对这一基础设施的需求。这将是心脏保护领域的一次范式转变。通过筛选有前景的疗法，并确定那些在相关实验模型中有效并因此最有可能对患者有效的重复性疗法，该联盟将极大地提高我们将基本发现合理转化为临床应用的能力。 这项建议解决了对NHLBI任务和整个公共卫生具有重大意义的一个问题，即未能将心脏保护的实验研究转化为临床治疗。在美国，缺血性心脏病是导致死亡和残疾的头号原因。由于每年约有130万美国人患有心肌梗死，其预后取决于心肌梗死的大小，因此，缩小心肌梗死面积将对他们的发病率和死亡率产生重大影响，从而对公众健康产生巨大影响。(摘要结束)

DESCRIPTION (provided by applicant): Ischemic heart disease causes -600,000 deaths/year (-20% of all deaths). An estimated 1.3 million Americans have a myocardial infarction every year; because their prognosis is determined by the size of the infarct, reducing infarct size is of paramount importance to alleviate morbidity and mortality. For more than 30 years the NHLBI has invested enormous resources (at least several hundred million dollars) in preclinical studies aimed at developing infarct-sparing therapies, and several hundred (if not thousands) therapies have been claimed to limit infarct size in preclinical models. Unfortunately, due to methodological problems, this enormous investment has not produced any notable clinical application, and no cardioprotective therapy is currently available for clinical use. After >30 years of futile efforts, a new approach is needed to overcome the problems that have impeded the translation of cardioprotective therapies. The time has come to apply to preclinical research the same standards of scientific rigor that are applied to clinical trials. Using the clinical trials networks established by the NHLBI as a model for developing a collaborative infrastructure for research sharing, we propose a preclinical consortium that will operate in a manner analogous to a clinical network. Six Institutions will work together to conduct blinded, randomized, and adequately powered studies using a rigorous design, full dose-response analyses, optimal statistical methods, independent data analysis and statistical Cores, histology, plasma biomarkers, and relevant animal models (including conscious animals and models of comorbidities) in three species (mouse, rabbit, pig). To ensure reproducibilitv. each study will be performed in two Centers using identical protocols. This unique infrastructure will enable rigorous preclinical evaluation of promising cardioprotective therapies and will serve the entire scientific community (both in academia and in biomedical industry), thereby constituting a public resource. Proposals for studying therapies will be solicited from the entire scientific community and reviewed by an independent Protocol Review Committee, which will select those that will be implemented. At least 3 therapies/year will be tested. The consortium structure will ensure that it will be a true public resource available to all interested investigators and that all proposed studies will be evaluated in an equitable fashion. The need for this infrastructure is attested to by 30 letters (Appendix). This will be a paradigm shift in cardioprotection. By screening promising therapies and identifying those that are reproduciblv effective in relevant experimental models and, thus, most likely to be effective in patients, the consortium will dramatically advance our ability to rationally translate basic findings into clinical use. This proposal addresses an issue that has major importance for the NHLBI mission and for public health at large, namely, the failure to translate experimental studies of cardioprotection into clinical therapies. Ischemic heart disease is the number one cause of death and disability in America. Since ~1.3 million Americans have a myocardial infarction each year and their prognosis is determined by the size of the infarct, reducing infarct size will have a major impact on their morbidity and mortality and, thus, enormous implications for public health. (End of Abstract)