Modulation of microRNA pathways by gemfibrozil in predementia Alzheimer disease

描述（由申请人提供）：我们的初步数据表明miR-107在AD发病机制中起重要作用。在培养的H4细胞中，Fibrates （PPAR激动剂）增加miR-107的表达，并下调BACE1蛋白（一种促进AD的必需酶）。我们计划测试我们的假设，并评估基于这种新型microRNA （miRNA）途径的阿尔茨海默病（AD）的潜在治疗方法。阿尔茨海默病动物模型的临床前研究一直受到在人类中未见的物种特异性肝毒性的阻碍。因此，人体临床试验是必要的，以验证这一重要的假设，关于阿尔茨海默病贝特类药物的疾病调节特性。具体来说，我们建议在一项平行设计、双盲、安慰剂对照研究中，评估吉非齐对微rna调节AD机制的安全性和有效性。我们将评估gemfibrozil对miR- 107的安全性和靶向性，以及相关AD生物标志物的改变。吉非罗齐是一种安全的口服药物，fda批准用于治疗老年人高脂血症。FDA已经为这些研究指明了IND豁免状态。本研究旨在为未来贝特类药物在阿尔茨海默病和阿尔茨海默病预防试验中的大规模II期和III期研究提供基础，并且是我们所知的第一次通过影响新型微rna途径来调节阿尔茨海默病的疾病进展的尝试。因此，拟议的研究代表了一种前沿的、数据驱动的、对一种新的疾病相关途径的探索，可能为我们在发展中国家和发达国家针对这一主要卫生优先事项的全球努力带来希望。

DESCRIPTION (provided by applicant): Our preliminary data indicate that miR-107 plays an important role in AD pathogenesis. Fibrates (PPAR agonists) increase miR-107 expression, and down-regulated BACE1 protein, an essential enzyme contributing to AD, in cultured H4 cells. We plan to test our hypotheses and evaluate a potential therapy for Alzheimer's disease (AD) based on this novel microRNA (miRNA) pathway. Preclinical work in this area using animal models of AD has been thwarted by the species-specific hepatotoxicity not seen in humans. Thus, human clinical trials are necessary to test this important hypothesis on the disease modifying properties of fibrates in AD. Specifically, we propose an evaluation of the safety and efficacy of gemfibrozil administration on micro-RNA modulation of AD mechanisms in a parallel-design, double- blind, placebo-controlled study. We will evaluate both safety and target engagement of miR- 107 by gemfibrozil as well as alterations in relevant AD biomarkers. Gemfibrozil is a safe, orally- administered, FDA-approved drug for treatment of hyperlipidemia in aged individuals. The FDA has indicated IND exemption status for these studies. This study is designed to provide the foundation for future large-scale Phase II & III studies of fibrates in AD and AD prevention trials and represents the first attempt we are aware of designed to modulate disease progression in AD through influences on novel micro-RNA pathways. As such the proposed study represents a cutting-edge, data-driven, exploration of a novel disease relevant pathway that may hold promise for our global efforts targeting this major health priority among developing and developed nations.