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

• 批准号: 8643890
• 负责人: MARY JO LADU
• 金额: $ 23.36万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 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/8643890
• 关键词: ATP-Binding Cassette Transporters; Accounting; Adverse effects; Age; Aging; Agonist; Alleles; Alzheimer' s Disease; Alzheimer' 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; 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; 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

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）：阿尔茨海默氏病（AD）的主要遗传危险因素是载脂蛋白E（APOE）的APOE4基因的遗传（APOE），使用APOE4+/+增加了大约15倍的风险，而APOE2的遗传降低了风险。 APOE4载体占AD患者的一半以上，并且对某些治疗干预措施表现出差异反应，这可能导致临床试验的失败。由APOE4引起的AD的惊人HGH风险和用淀粉样蛋白β肽（ABETA）进行协同作用的明确证据表明，迫切需要开发融合APOE基因型和β病理学的治疗方法。最近，据报道，RXR激动剂Bexarotene（Bex）会增加小鼠 - 乔apoe水平，减少几小时内可溶性ABETA，三天后不溶性abeta，并恢复表达家族性AD突变的转基因小鼠的认知。但是，将小鼠数据推外向AD患者是有问题的，因为研究未纳入人类APOE同工型。遗传数据表明，降低人类APOE水平实际上降低了Abeta病理。此外，APOE4代表了通过体外和体内突触活力标记所评估的功能的有毒功能增益。我们的假设是RXR激动剂诱导的Abeta病理衰减是通过APOE基因型差异调节的。这项拟议的研究的结果将既及时又至关重要，因为BEX目前正在进入1期临床试验。并将告知未来关于RXR激动剂的临床试验的设计，包括剂量和纳入APOE4受试者。 BEX将与LG268并行研究，因为它具有更大的RXR选择性（超过RAR），而GRT63是一种新型的同源物。尽管所有三种RXR激动剂都具有高口服脑生物利用度，但LG268和GRT63具有改善的理化特征。 AIM 1将建立BEX，LG268和GRT63的预测性PK/PD和DMPK特性，以指导体内策略来测试Efad-TG小鼠中的治疗范例（AIM 2），一种创新的模型，一种创新的模型，该模型表达人类ApoE和Expackress Abeta Abeta Abeta Abeta 12。 （LXR-luciferase构建体），RXR生物标志物验证（ABCA1/ABCG1，APOE，诱导细胞因子IL-1β和TNF-Alpha）在多个细胞系中，并鉴定每种激动剂的有效口服剂量。将测量肝微粒体和PK和体重体重的代谢稳定性。 AIM 2将使用AIM 1中确定的有效剂量在EFAD小鼠中确定RXR激动剂在EFAD小鼠中的治疗功效，并比较E4FAD和E3FAD小鼠。提出RXR介导的APOE3升高是有益的，其特征是降低了β病理学和炎性细胞因子，以及突触蛋白丧失和行为缺陷的逆转。但是，ABCA1/ABCG1的RXR诱导可能会在APOE4载体中提供更大的净有益作用，因为APOE4的脂化可能较少，与APOE3相比，功能的部分损失。这些研究将确定在高度创新的AD动物模型中，在APOE3和APOE4存在下RXR激动剂的功效。