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

ABCA1 激动剂作为 AD 新型疗法的临床前评估

• 批准号: 8959989
• 负责人: MARY JO LADU
• 金额: $ 19.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8959989
• 关键词: ATP binding cassette transporter 1; Address; Adverse effects; Aging; Agonist; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Apolipoprotein E; Arteries; Behavioral; Bexarotene; Biological Markers; Brain; Brain region; Cardiovascular Diseases; Caring; Clinical; Clinical Trials; Cognition; Complex; Data; Dementia; Development; Disease; Dose; Elderly; Epidemic; Female; Genetic; Goals; Health; Hepatomegaly; Hepatotoxicity; Human; In Vitro; Inflammation; Institutes; Intervention; Lipids; Lipoproteins; Maximum Tolerated Dose; Memory; Methods; Mus; Neurotoxins; Nuclear Receptors; Pathology; Pathway interactions; Patients; Peptides; Peripheral; Phase I Clinical Trials; Phenotype; Population; Prevention; Protein Isoforms; Proteins; Protocols documentation; RXR; Research; Risk; Role; Staging; Symptoms; Synapses; Testing; Therapeutic; Time; Transgenic Mice; Translations; Treatment Protocols; United States; Validation; apolipoprotein E-3; apolipoprotein E-4; base; cost; drug discovery; gain of function; genetic risk factor; improved; in vivo; innovation; loss of function; male; meetings; mouse model; neuron loss; novel; novel therapeutics; oAβ; overexpression; pre-clinical; prevent; protein expression; repaired; response; targeted treatment; therapeutic target

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.

描述（由适用提供）：APOE4是零星阿尔茨海默氏病（AD）的最大遗传危险因素，与APOE3相比，风险增加到15倍。由于APOE4载体在临床试验中可能异常反应，有时是负面反应，因此缺乏针对APOE4诱导的AD风险的机械途径的治疗疗法。遗传证据支持淀粉样蛋白 - 肽（Aß），尤其是Aß42作为AD中的致病药物的作用， 可溶性寡聚聚集体（OAß）被公认为近端神经毒素。正如一致的证据表明，表明载脂蛋白E（APOE）对实心Aß水平的特异性调节可能会带来APOE4诱导的AD风险，我们的治疗目标是开发基于APOE的方法以降低OAß水平。通过开发新型ELISA和新的EFAD小鼠模型（过表达Aß42并表达人APOE），我们已经解剖了APOE4与固体Aß水平增加之间相关性的潜在途径。我们的数据表明，与APOE3相比，APOE4的脂蛋白缔合/脂质降低，导致APOE4/Aß复合物的水平较低，而实心OAß水平较高，损害了突触可行性。 ABCA1是检验该假设的有前途的治疗靶标，因为ABCA1是CNS中脂质脂肪蛋白的主要转运蛋白。使用EFAD小鼠，我们最近证明，用RXR激动剂进行1周的治疗增加了ABCA1水平，APOE4脂质和可溶性APOE4/Aß复合物水平，同时降低了固体Aß水平并增加突触蛋白水平。但是，在治疗时患有低Aß病理学的大脑区域（E3FAD和E4FAD小鼠）中，未观察到有益的效果，并且实际上增加了实心Aß的水平。尽管这些数据为ABCA1提供了目标验证，但归因于严重的肝肿大的有害脱靶效应，在长期治疗方案中限制了RXR激动剂效用。动脉疗法开发了包括COGPEP B在内的新型ABCA1激动剂，用于治疗周围心血管疾病。 COGPEP B表现出高效力可在体外增加ABCA1的活性和水平，在体内具有高最大耐受剂量，并且是脑穿透性的，其浓度比此处提出的剂量低于体外KM的浓度高2-6倍。此外，初步数据表明，与APOE3-TR相比，COGPEP B增加了突触蛋白水平并改善APOE4靶向替代（TR）小鼠的记忆。该提案首次评估COGPEP B在治疗中（AIM 1）和预防（AIM 2）方案的CNS效应。为了实现卫生部设定的雄心勃勃的目标，以防止或有效治疗2025年的AD，需要新颖的治疗候选者来靶向APOE4诱导的AD风险的机制。该R21通过在相关的EFAD小鼠中对CogPep B的临床前重新利用来测试这种治疗性。从药物发现的角度来看，COGPEP B的重新利用将有助于成功地转化为临床试验，n比目前的核接收器激动剂更安全。