Therapeutic Efficacy of Intranasal WGA-GLP1 in AD

描述（由申请人提供）：阿尔茨海默病（AD）是一个全球性的健康危机。仅在美国，就有540万美国人患有阿尔茨海默病，如果没有发现有效的治疗方法，这个数字可能会上升到1600万。新出现的证据表明2型糖尿病（T2DM）和AD之间存在因果关系。T2DM和AD均表现为高血糖、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，逻辑上导致胰岛素治疗。然而，由于胰岛素与胰岛素降解酶（IDE）的竞争，胰岛素可能产生低血糖和升高Ass。因此，除胰岛素外，降低高血糖的方法正在出现。其中一种方法是使用肠促胰岛素——一组肠道激素，如胰高血糖素样肽1 (GLP1)，在高血糖时刺激胰岛素释放，同时防止低血糖和维持血糖。GLP1是一种神经保护作用，通过表达在神经元上的GLP1受体（GLP1R）起作用，已知可改善学习和记忆。GLP1被二肽基肽酶4 （DPP-4）降解，在人体中半衰期为1-2分钟，这导致了DPP-4耐药更稳定、持续时间更长的GLP1模拟物，如Exendin-4 （Byetta）和利拉鲁肽（Victoza）。然而，据报道，长期系统使用这些GLP1类似物会导致胰腺炎和肾功能衰竭。为了避免这些不利因素，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与小麦胚芽凝集素（WGA）结合的新修饰（WGA是一种生物来源的非免疫和无毒糖蛋白）。WGA与GLP1结合不仅会增强GLP1的鼻内递送，而且还会发挥附加的胰岛素作用

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.