Detoxification Depot for Beta-amyloid peptides

描述(申请人提供)：长期目标是开发一种治疗阿尔茨海默病的有效方法，通过使用一种皮下水凝胶来识别、浓缩和消除β-淀粉样蛋白(Abeta)肽，从而阻止大脑中斑块的沉积。在Abeta结合元件的存在下，将亲核修饰的聚乙二醇(PEG)与亲电泳改性的交联剂混合后，在约1分钟内从注射溶液中原位形成水凝胶。这种水凝胶会缓慢而稳定地积聚ABeta，起到“水槽”的作用，将这些有毒的多肽拉过血脑屏障。这种下沉效应是基于逆转录多肽(RIP)聚集体Phe-Phe-Val-Leu-Lys提供的强大而特异的结合，该聚集体将共价连接到水凝胶中的聚乙二醇链。我们已经开发了水凝胶作为药物输送系统，我们已经证明了RIP结合靶向Abeta的能力。目前的提议是我们之前研究的逻辑应用，目的是开发一个最终可能有助于控制和/或治愈阿尔茨海默氏症的“解毒库”。第一阶段的目标是建立原则证明，我们可以将水凝胶用作 体外解毒库。第二阶段将涉及应用这个仓库来降低体内实验小鼠模型中的Abeta浓度。最终目标将是抑制小鼠模型中的斑块沉积。

DESCRIPTION (provided by applicant): The long-term goal is to develop an effective therapy for Alzheimer's disease, by using a subcutaneous hydrogel to recognize, concentrate and eliminate beta-amyloid (Abeta) peptides and thereby halt deposition of plaque in the brain. The hydrogel forms in situ from an injected solution within about 1 minute after mixing nucleophile-modified poly (ethylene glycol) (PEG) with electrophile-modified cross-linker in the presence of the Abeta binding element. The hydrogel will slowly and steadily accumulate ABeta, acting as a "sink" to draw these toxic peptides across the blood-brain barrier. This sink effect is based on the strong and specific binding provided by aggregates of the retro-inverso peptide (RIP), phe-phe-val-leu-lys, which will be covalently linked to PEG chains in the hydrogel. We already have developed the hydrogel as a drug delivery system and we have proven the capability of the RIP to bind target Abeta. The current proposal is a logic application of our previous research to develop a "detoxification depot" that may eventually help control and or cure Alzheimer's disease. The goal of Phase I is to establish proof-of-principle that we can use the hydrogel as a detoxification depot in vitro. Phase II will concern applying this depot to lowering the concentration of Abeta using an experimental mouse model, in vivo. The final goal will be inhibition of plaque deposition in the mouse model.