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Potential ApoE Isoform-Specific Detrimental Effects of RXR Agonists in Alzheimer'

RXR 激动剂对阿尔茨海默病的潜在 ApoE 同工型特异性有害影响

基本信息

批准号：
8917836
负责人：
MARY JO LADU
金额：
$ 18.93万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8917836
关键词：
ATP binding cassette transporter 1 ATP-Binding Cassette Transporters Accounting Adverse effects Age Aging Agonist Alleles Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Animal Model Apolipoprotein E Behavioral Bexarotene Biological Availability Biological Markers Body Weight Brain Caring Cell Line Cells Characteristics Clinical Clinical Trials Cognition DNA Data Dementia Development Disease Progression Dose Elderly Epidemic Exhibits Failure Future Genes Genetic Genotype Goals Health HepG2 Hepatocyte Homologous Gene Hour Human In Vitro Inflammation Inflammatory Institutes Interleukin-1 Liver Microsomes Luciferases Measures Mediating Mediator of activation protein Metabolic Modeling Mus Mutation Neuroglia Oral Pathology Pathway interactions Patients Peptides Pharmaceutical Preparations Phase I Clinical Trials Population Presenile Alzheimer Dementia Prevention Property Protein Isoforms Proteins RXR Reporting Response Elements Risk Risk Factors Safety Synapses TNF gene Testing Therapeutic Therapeutic Intervention Time Toxic effect Transgenic Mice Treatment Efficacy Tumor Necrosis Factor-alpha United States Up-Regulation Validation Work apolipoprotein E-3 apolipoprotein E-4 attenuation base cancer therapy conditioned fear cost cytokine design dosage familial Alzheimer disease gain of function genetic risk factor high risk human TNF protein improved in vivo innovation loss of function macrophage mouse model new therapeutic target novel overexpression response success treatment duration

项目摘要

DESCRIPTION (provided by applicant): The primary genetic risk factor for Alzheimer's disease (AD) is inheritance of the APOE4 gene for apolipoprotein E (apoE), increasing the risk approximately 15-fold with APOE4+/+, whereas inheritance of APOE2 reduces risk. APOE4 carriers account for more than half of AD patients, and exhibit a differential response to certain therapeutic interventions, which can contribute to the failure of clinical trials. The strikingly hgh-risk for AD caused by APOE4 and clear evidence for synergistic actions with amyloid-beta peptide (Abeta), point to the urgent need to develop therapeutic approaches that incorporate the APOE genotype and A beta pathology. Recently, the RXR agonist, bexarotene (BEX), was reported to increase mouse-apoE levels, decrease soluble Abeta within hours, insoluble Abeta after three days, and restore cognition in transgenic mice expressing familial AD mutations. However, extrapolation of the mouse data to AD patients is problematic since the studies did not incorporate human-apoE isoforms. Genetic data demonstrates that lowering human-apoE levels actually decreases Abeta pathology in; furthermore, APOE4 represents a toxic gain of function as assessed by markers of synapse viability in vitro and in vivo. Our hypothesis is that RXR agonist-induced attenuation of Abeta pathology is differentially modulated by APOE genotype. Results from this proposed study will be both timely and critical, as BEX is currently entering phase 1 clinical trials; and will inform the design of future clinical trials on RXR agonists, including dosage and the inclusion of APOE4 subjects. BEX will be studied in parallel with LG268 as it has greater RXR selectivity (over RAR), and GRT63, a novel homologue. While all three RXR agonists have high oral brain bioavailability, LG268 and GRT63 have improved physicochemical characteristics. Aim 1 will establish predictive PK/PD and DMPK properties for BEX, LG268 and GRT63 to direct the in vivo strategy to test treatment paradigms in EFAD-Tg mice (Aim 2), an innovative model which expresses human APOE and overexpress Abeta 42. Aim 1 will determine the PK/PD for RXR agonists in vitro and in vivo, by establishing target engagement (LXRE-luciferase construct), RXR biomarker validation (ABCA1/ABCG1, apoE, induction of cytokines IL-1 beta and TNF-alpha) in multiple cell lines, and identifying an effectiv oral dose for each agonist. Metabolic stability in liver microsomes and PK and body weight in vivo will be measured. Aim 2 will determine the therapeutic efficacy of RXR agonists in EFAD mice using efficacious doses identified in Aim 1, comparing E4FAD and E3FAD mice. The RXR-mediated elevation of APOE3 is proposed to be beneficial, characterized by reduced A beta pathology and inflammatory cytokines, and reversal of synaptic protein loss and behavioral deficits. However, RXR induction of ABCA1/ABCG1 may provide a greater net beneficial effect in APOE4 carriers, as apoE4 may be less lipidated, resulting in a partial loss of function compared with apoE3. These studies will determine the efficacy of RXR agonists in the presence of APOE3 and APOE4 in a highly innovative animal model of AD.

描述（由申请人提供）：阿尔茨海默病 (AD) 的主要遗传风险因素是载脂蛋白 E (apoE) 的 APOE4 基因遗传，APOE4+/+ 的风险增加约 15 倍，而 APOE2 的遗传则降低风险。 APOE4 携带者占 AD 患者的一半以上，并且对某些治疗干预措施表现出不同的反应，这可能导致临床试验的失败。 APOE4 引起 AD 的极高风险以及与淀粉样β肽 (Abeta) 协同作用的明确证据表明，迫切需要开发结合 APOE 基因型和 Aβ 病理学的治疗方法。最近，据报道，RXR 激动剂贝沙罗汀 (BEX) 可以增加小鼠 apoE 水平，在数小时内降低可溶性 Abeta，在三天后降低不溶性 Abeta，并恢复表达家族性 AD 突变的转基因小鼠的认知能力。然而，将小鼠数据外推到 AD 患者是有问题的，因为这些研究没有纳入人类 apoE 亚型。遗传数据表明，降低人类 apoE 水平实际上可以减少 Abeta 病理；此外，根据体外和体内突触活力标记物的评估，APOE4 代表了毒性功能增益。我们的假设是 RXR 激动剂诱导的 Abeta 病理减弱受到 APOE 基因型的差异调节。这项拟议研究的结果既及时又关键，因为 BEX 目前正在进入 1 期临床试验；并将为 RXR 激动剂未来临床试验的设计提供信息，包括剂量和 APOE4 受试者的纳入。 BEX 将与 LG268 和 GRT63（一种新型同系物）并行研究，因为它具有更高的 RXR 选择性（相对于 RAR）。虽然所有三种 RXR 激动剂都具有较高的口服脑生物利用度，但 LG268 和 GRT63 改善了理化特性。目标 1 将为 BEX、LG268 和 GRT63 建立预测 PK/PD 和 DMPK 特性，以指导体内策略测试 EFAD-Tg 小鼠的治疗范例（目标 2），这是一种表达人类 APOE 并过度表达 Abeta 42 的创新模型。目标 1 将通过建立靶标参与来确定 RXR 激动剂的体外和体内 PK/PD。（LXRE-荧光素酶构建体），在多个细胞系中验证 RXR 生物标志物（ABCA1/ABCG1、apoE、细胞因子 IL-1β 和 TNF-α 的诱导），并确定每种激动剂的有效口服剂量。将测量肝微粒体的代谢稳定性以及体内 PK 和体重。目标 2 将使用目标 1 中确定的有效剂量确定 RXR 激动剂对 EFAD 小鼠的治疗效果，比较 E4FAD 和 E3FAD 小鼠。 RXR 介导的 APOE3 升高被认为是有益的，其特征是减少 Aβ 病理和炎症细胞因子，并逆转突触蛋白损失和行为缺陷。然而，ABCA1/ABCG1 的 RXR 诱导可能在 APOE4 携带者中提供更大的净有益效果，因为 apoE4 可能脂化程度较低，导致与 apoE3 相比部分功能丧失。这些研究将在高度创新的 AD 动物模型中确定 RXR 激动剂在 APOE3 和 APOE4 存在下的功效。