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(由申请人提供)：ApoE4是散发性阿尔茨海默病(AD)的最大遗传风险因素，与APOE3相比，风险增加15倍。由于APOE4携带者可以在临床试验中异常反应，有时是负面的，因此严重缺乏针对APOE4诱导的AD风险的机制途径的治疗方法。遗传证据支持淀粉样多肽(A？)的作用，特别是A？42，作为AD的致病因子， 可溶寡聚体被认为是可能的近端神经毒素。一致的证据表明，载脂蛋白E(ApoE)异构体特异性调节可溶性Aü水平可能会导致APOE4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OAç水平。在新的ELISA和新的EFAD小鼠模型(过表达Aü42和表达人APOE)的发展的推动下，我们已经剖析了apoE4和可溶性Aü水平增加之间潜在的关联途径。我们的数据表明，与apoE3相比，apoE4的脂蛋白结合/脂化作用减少，导致apoE4/A？复合体水平较低，而可溶性OA？水平较高，从而影响突触的活性。ABCA1是验证这一假说的一个有希望的治疗靶点，因为ABCA1是中枢神经系统中脂类到含apoE的脂蛋白的主要转运体。在EFAD小鼠身上，我们最近证明，RXR激动剂治疗1周后，ABCA1水平、apoE4脂化水平和可溶性apoE4/Aç复合体水平增加，而可溶性Aü水平降低，突触蛋白水平增加。然而，在治疗时Aü病理低的脑区(E3FAD和E4FAD小鼠)，没有观察到有益的效果，而可溶性Aü水平实际上增加了。虽然这些数据为ABCA1提供了靶点验证，但由于严重的肝肿大，有害的非靶点效应限制了RXR激动剂在长期治疗方案中的应用。动脉治疗公司开发了新型ABCA1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ABCA1活性和水平的高效力，在体内具有较高的最大耐受量，并且是脑透性的，其浓度是体外KM的2-6倍，剂量低于本文所建议的剂量。此外，初步数据表明，与APOE3-TR相比，CogPeP B提高了APOE4靶向替换(TR)小鼠的突触蛋白水平，并改善了小鼠的记忆力。这项建议将首次评估CogPep B在治疗(目标1)和预防(目标2)方案中对雄性和雌性EFAD小鼠的中枢神经系统影响。为了实现卫生部设定的到2025年预防或有效治疗阿尔茨海默病的雄心勃勃的目标，需要新的治疗候选药物来靶向载脂蛋白4诱导的阿尔茨海默病风险的机制(S)。这款R21通过在AD相关的EFAD小鼠身上重新调整CogPep B的临床前用途来测试这种治疗方法。从药物发现的角度来看，CogPep B的重新用途将有助于成功地转化为临床试验，替代比目前的核受体激动剂更安全的药物。