Modulation of microRNA pathways by gemfibrozil in predementia Alzheimer disease

描述(申请人提供)：我们的初步数据表明miR-107在AD的发病机制中发挥重要作用。贝特类(PPAR激动剂)增加培养的H4细胞miR-107的表达，下调BACE1蛋白的表达，BACE1蛋白是导致AD的关键酶。我们计划检验我们的假设，并评估基于这种新的microRNA(MiRNA)途径治疗阿尔茨海默病(AD)的潜在疗法。使用AD动物模型在这一领域的临床前工作因人类未见的物种特异性肝毒性而受挫。因此，有必要进行人体临床试验，以验证贝特类药物在AD中改善疾病的这一重要假说。具体地说，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罗齐给药对微RNA调节AD机制的安全性和有效性。我们将评估吉非罗齐对miR-107的安全性和靶向性，以及相关AD生物标志物的变化。吉非罗齐是FDA批准的安全的口服药物，用于治疗老年人的高脂血症。FDA已经表明了这些研究的IND豁免地位。这项研究旨在为未来贝特类药物在AD和AD预防试验中的第二和第三阶段大规模研究提供基础，并代表了我们所知的旨在通过影响新的microRNA途径来调节AD疾病进展的第一次尝试。因此，拟议的研究代表了对一种与疾病相关的新途径的尖端、数据驱动的探索，这可能会为我们在发展中国家和发达国家中针对这一主要健康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.