Preclinical assessment of an ABCA1 agonist as a novel therapeutic for AD

描述（由申请人提供）：APOE 4是散发性阿尔茨海默病（AD）的最大遗传风险因素，与APOE 3相比，风险增加高达15倍。由于APOE 4携带者在临床试验中可能产生不良反应，有时是负面的，因此严重缺乏针对APOE 4诱导AD风险的机制途径的治疗方法。遗传学证据支持淀粉样蛋白-β肽（A β），特别是A β 42作为AD的致病因子的作用， 可溶性低聚物聚集体（oA）被认为是可能的近端神经毒素。由于一致的证据表明，载脂蛋白E（apoE）亚型特异性调节可溶性A β水平可能赋予APOE 4诱导的AD风险，我们的治疗目标是开发基于apoE的方法来降低A β水平。通过开发新的ELISA和新的EFAD小鼠模型（过表达A β 42和表达人APOE），我们已经剖析了apoE 4和可溶性A β水平增加之间相关性的潜在途径。我们的数据表明，与apoE 3相比，apoE 4的脂蛋白结合/脂化减少，导致较低水平的apoE 4/ApoE 4复合物和较高水平的可溶性apoE 4，损害突触活力。ABCA 1是一个有前途的治疗目标，用于测试这一假设，因为ABCA 1是一个主要的转运体脂质载脂蛋白E在中枢神经系统中。使用EFAD小鼠，我们最近证明，用RXR激动剂治疗1周可增加ABCA 1水平、apoE 4脂化和可溶性apoE 4/ApoE 4复合物水平，同时降低可溶性ApoE 4水平并增加突触蛋白水平。然而，在治疗时具有低AAF病理学的脑区域（E3 FAD和E4 FAD小鼠两者）中，未观察到有益作用，并且可溶性AAF的水平实际上增加。虽然这些数据为ABCA 1提供了靶点验证，但由于严重肝肿大而导致的有害脱靶效应限制了RXR激动剂在长期治疗方案中的效用。动脉治疗公司开发了新型ABCA 1激动剂，包括CogPep B，用于治疗外周心血管疾病。CogPep B在体外表现出提高ABCA 1活性和水平的高效力，在体内具有高的最大耐受剂量，并且是脑渗透剂，在低于本文提出的剂量下，其浓度是体外KM的2-6倍。此外，初步数据表明，与APOE 3-TR相比，CogPeP B增加了APOE 4靶向替代（TR）小鼠的突触蛋白水平并改善了记忆。该提案将首次评估CogPep B在雄性和雌性EFAD小鼠中治疗（目标1）和预防（目标2）方案中的CNS效应。为了实现卫生部设定的到2025年预防或有效治疗AD的宏伟目标，需要新的治疗候选物来靶向APOE 4诱导的AD风险的机制。该R21通过CogPep B在AD相关EFAD小鼠中的临床前再利用来测试这种治疗剂。从药物发现的角度来看，CogPep B的再利用将有助于成功地转化为临床试验，这比目前的核受体激动剂更安全。

DESCRIPTION (provided by applicant): APOE4 is the greatest genetic risk factor for sporadic Alzheimer's disease (AD), increasing risk up to 15-fold compared to APOE3. As APOE4 carriers can respond anomalously in clinical trials, sometimes negatively, there is a critical lack of therapeutics targeting mechanistic pathways of APOE4-induced AD risk. Genetic evidence supports the role of amyloid-ß peptide (Aß), particularly Aß42, as a causative agent in AD, with soluble oligomeric aggregates (oAß) recognized as the likely proximal neurotoxins. As congruent lines of evidence indicate that apolipoprotein E (apoE) isoform-specific modulation of soluble Aß levels may impart APOE4-induced AD risk, our therapeutic goal is to develop apoE-based approaches to reduce oAß levels. Enabled by the development of the novel ELISAs and the new EFAD mouse model (overexpressing Aß42 and expressing human APOE), we have dissected potential pathways underlying the correlation between apoE4 and increased levels of soluble Aß. Our data demonstrate that compared to apoE3, lipoprotein- association/lipidation of apoE4 is reduced, resulting in lower levels of apoE4/Aß complex and higher levels of soluble oAß, compromising synaptic viability. ABCA1 is a promising therapeutic target for testing this hypothesis because ABCA1 is a major transporter of lipid to apoE-containing lipoproteins in the CNS. Using EFAD mice, we recently demonstrated that 1-week treatment with RXR agonists increased ABCA1 levels, apoE4 lipidation, and soluble apoE4/Aß complex levels, while lowering soluble Aß levels and increasing synaptic protein levels. However, in brain regions with low Aß pathology at time of treatment (both E3FAD and E4FAD mice), no beneficial effects were observed and levels of soluble Aß were actually increased. While these data provide target validation for ABCA1, the detrimental off-target effects, attributed to severe hepatomegaly, limit RXR agonist utility in long-term treatment protocols. Artery Therapeutics developed novel ABCA1 agonists, including CogPep B, for the treatment of peripheral cardiovascular disease. CogPep B demonstrates high potency for increasing the activity and levels of ABCA1 in vitro, has a high maximal tolerated dose in vivo and is brain penetrant with concentrations 2-6-fold above the in vitro KM at a dose lower than that proposed herein. In addition, preliminary data demonstrate that CogPeP B increases synaptic protein levels and improves memory in APOE4-targeted replacement (TR) mice compared to APOE3-TR. For the first time, this proposal will assess the CNS effects of CogPep B in treatment (Aim 1) and prevention (Aim 2) protocols in male and female EFAD mice. To meet the ambitious goal set by the Department of Health to prevent or effectively treat of AD by 2025 requires novel therapeutic candidates to target mechanism(s) of APOE4-induced AD risk. This R21 tests such a therapeutic through the preclinical repurposing of CogPep B in the AD-relevant EFAD mice. From a drug discovery standpoint, the repurposing of CogPep B will facilitate successful translation to clinical trials, n alternative safer than current nuclear receptor agonists.