Therapeutic Efficacy of Intranasal WGA-GLP1 in AD

鼻内WGA-GLP1治疗AD的疗效

• 批准号: 8640998
• 负责人: NEELIMA CHAUHAN
• 金额: $ 19.74万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8640998
• 关键词: Achievement; Afferent Neurons; Alzheimer' s Disease; American; Asses; Axonal Transport; Binding; Biological; Blood Glucose; Brain; Calculi; Clinical; Cognition; Cognitive deficits; Complex; Development; Dipeptidyl Peptidases; Disease; Enzymes; Exhibits; Functional disorder; Gluconeogenesis; Glucosamine; Glucose; Glutamates; Glycoproteins; Goals; Growth Factor; Half-Life; Health; Hepatic; Hormones; Human; Hyperglycemia; Hypoglycemia; IRS1 gene; Immunotherapeutic agent; Insulin; Insulin Receptor; Insulin Resistance; Insulinase; Intervention; Intranasal Administration; Kidney Failure; Label; Learning; Link; Membrane Glycoproteins; Memory; Modification; Mus; Neurodegenerative Disorders; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nose; Pancreatitis; Reporting; Resistance; Route; Sialic Acids; Structure of mucous membrane of nose; Synapses; Testing; Therapeutic; Transgenic Mice; Translations; Treatment Efficacy; Validation; Wheat Germ Agglutinins; age related; analog; desensitization; effective therapy; exenatide; global health; glucagon-like peptide; improved; liraglutide; mimetics; mouse model; novel; pre-clinical; prevent; receptor; repaired; research clinical testing; uptake

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a global health crisis. In US alone, ~5.4 million Americans are afflicted with AD, and this number may escalate up to ~16 million if effective treatments are not discovered. Emerging evidence indicates a causal link between type 2 diabetes (T2DM) and AD. Both T2DM and AD exhibit hyperglycemia, insulin resistance and insulin receptor(s) (IRS1/2) dysfunction. Insulin acts as a neuroprotective factor, supports neuronal repair, dendritic sprouting and differentiation which logically led to insulin therapy. However, Insulin is likely to produce hypoglycemia and elevate Ass due to its competition with insulin degrading enzyme (IDE) that degrades both insulin and Ass. Therefore, approaches that reduce hyperglycemia other than insulin are emerging. One such approach is the use of incretins-a group of gut hormones-such as Glucagon-like peptide 1 (GLP1), that stimulates insulin release during hyperglycemia, while simultaneously preventing hypoglycemia and maintaining euglycemia. GLP1 is neuroprotective acting via GLP1 receptors (GLP1R) expressed on neurons and is known to improve learning and memory. GLP1 is degraded by dipeptidyl- peptidase 4 (DPP-4) with a half life of 1-2 min in humans, which resulted in the development of DPP-4 resistant more stable and longer lasting GLP1 mimetics such as Exendin-4 (Ex-4) (Byetta) and Liraglutide (Victoza). However, long-term systemic use of these GLP1 analogues is reported to cause pancreatitis and renal failure. In order to circumvent these adversities, we propose intranasal route of delivery of GLP1 which is previously shown to be successful, but with the novel modification of conjugating GLP1 with wheat germ agglutinin (WGA)-a biologically-derived non-immune and non-toxic glycoprotein. WGA conjugation to GLP1 not only will enhance intranasal delivery of GLP1, but will also exert additive insulinotropic effects and thus will validate advanced incretin therapy for AD. We have already tested the feasibility of intranasal administration of WGA- labeled GLP1 (WGA-GLP1) to the brain in 5XFAD mice modeling AD, which strengthens successful achievement of proposed aims. This project will test the hypothesis that Intranasal delivery of WGA conjugated GLP1 (WGA-GLP1) will more efficiently prevent and reverse AD-like pathocognition than the unconjugated GLP1 (GLP1) in 5XFAD mice. If successful, this project has great potential for clinical translation.

描述（由申请人提供）：阿尔茨海默病（AD）是一种全球性健康危机。仅在美国，就有大约 540 万美国人患有 AD，如果没有找到有效的治疗方法，这个数字可能会上升到大约 1600 万。新的证据表明 2 型糖尿病 (T2DM) 和 AD 之间存在因果关系。 T2DM 和 AD 均表现出高血糖、胰岛素抵抗和胰岛素受体 (IRS1/2) 功能障碍。胰岛素作为一种神经保护因子，支持神经元修复、树突发芽和分化，这在逻辑上导致了胰岛素治疗。然而，由于胰岛素与同时降解胰岛素和 Ass 的胰岛素降解酶 (IDE) 竞争，因此很可能导致低血糖和 Ass 升高。因此，除胰岛素外减少高血糖的方法正在出现。其中一种方法是使用肠降血糖素（一组肠道激素），例如胰高血糖素样肽 1 (GLP1)，它在高血糖期间刺激胰岛素释放，同时防止低血糖并维持血糖正常。 GLP1 通过神经元上表达的 GLP1 受体 (GLP1R) 发挥神经保护作用，已知可以改善学习和记忆。 GLP1 被二肽基肽酶 4 (DPP-4) 降解，在人体中的半衰期为 1-2 分钟，这导致开发出更稳定、更持久的 DPP-4 抗性 GLP1 模拟物，例如 Exendin-4 (Ex-4) (Byetta) 和利拉鲁肽 (Victoza)。然而，据报道，长期全身使用这些 GLP1 类似物会导致胰腺炎和肾衰竭。为了避免这些困难，我们提出了 GLP1 的鼻内递送途径，该途径先前已被证明是成功的，但采用了将 GLP1 与麦芽凝集素 (WGA)（一种生物来源的非免疫且无毒的糖蛋白）结合的新修饰。 WGA 与 GLP1 的结合不仅会增强 GLP1 的鼻内递送，而且还会发挥附加的促胰岛素作用 效果，从而验证先进的肠促胰素治疗 AD 的方法。我们已经在 5XFAD 小鼠模型 AD 中测试了向大脑鼻内施用 WGA 标记的 GLP1 (WGA-GLP1) 的可行性，这加强了所提出目标的成功实现。该项目将测试以下假设：在 5XFAD 小鼠中，鼻内递送 WGA 缀合的 GLP1 (WGA-GLP1) 将比未缀合的 GLP1 (GLP1) 更有效地预防和逆转 AD 样病理认知。如果成功，该项目具有巨大的临床转化潜力。