Detoxification Depot for b-amyloid peptides

描述（由申请人提供）：大脑中的神经毒性淀粉样斑块是阿尔茨海默病（AD）的特征，是由淀粉样前体蛋白的2个重叠片段（AB1-40和AB1-42）聚集形成的。这些a -肽可以穿过血脑屏障。我们的长期目标是开发一种有效的治疗阿尔茨海默病的方法，通过使用皮下水凝胶来识别、浓缩和消除AB （β淀粉样蛋白）肽，从而阻止斑块在大脑中的沉积。在I期研究中，我们开发并展示了一种专有的排毒凝胶，其中包含一种逆转录逆肽，它在体外就像一个“水池”，可以吸收AB肽。不可逆捕获AB的量和速率（体外2小时10 ug/100ul凝胶）可用于在人体内产生沉淀效应。我们现在在我们的II期提案中提出一种更有效、更特异性和更方便的治疗系统。除了使用我们在I期建立的排毒库外，我们计划改进AB捕获水凝胶配方，并在AD小鼠模型中评估其在体内的性能。本质上，含有由连接到聚合物的β结合元素组成的共轭物的溶液与交联试剂混合。这种溶液可以皮下注射，在那里它会迅速变成固体水凝胶。将评估排毒仓库降低大脑中a - β肽毒性聚集体水平的能力。几个版本的捕获肽将被包含在排毒凝胶中，并在阿尔茨海默病小鼠中测试其功效。评估参数包括免疫组织化学和生化测量。如果成功，这个解毒库将成为人类使用的候选物质。在大鼠、家兔和狗身上进行的安全性研究表明，水凝胶没有毒性。我们拥有“知识产权”的权利，并提出商业化计划，与一家制药公司合作进行未来评估。我们已经在商业化方面取得了进展。

DESCRIPTION (provided by applicant): The neurotoxic amyloid plaques in the brain, characteristic of Alzheimer's disease (AD), are formed by aggregation of 2 overlapping fragments (AB1-40 and AB1-42) of the amyloid precursor protein. These A-beta peptides can cross the blood-brain barrier. Our long-term goal is to develop an effective therapy for Alzheimer's Disease, by using a subcutaneous hydrogel to recognize, concentrate and eliminate AB (beta amyloid) peptides and thereby halt deposition of plaque in the brain. In the Phase I research, we developed and demonstrated a propreirtary detox gel encompassing a retro-inverso peptide which acts like a "sink" that draws the AB peptides, in vitro. The amount and rate of AB captured irreversibly (10 ug/100ul of gel in 2 hours, in vitro) could be used to produce the sink effect in humans. We now propose a more potent, specific and convenient therapeutic system in our Phase II proposal. In addition to using the detox depot we established in Phase I, we plan to improve the AB capture hydrogel formulation and evaluate its performance, in vivo, in a murine model of AD. Essentially, a solution containing a conjugate consisting of Abeta binding element linked to a polymer is mixed with a cross-linking reagent. This solution may be injected subcutaneously where it will rapidly become a solid hydrogel. The ability of the detox depot to decrease the level of the toxic aggregates of A-beta peptides in the brain will be evaluated. Several versions of the capture peptide will be included in the detox gels and tested for efficacy in AD mice. Evaluation parameters will include immunohistochemical and biochemical measurements. If successful, this detoxification depot will become a candidate for human use. Safety studies on the hydrogel performed in rats, rabbits and dogs demonstarted no toxicity. We hold rights to the 'intellectual property' and present a commercialization plan to perform future evaluations in partnership with a pharmaceutical firm. We have already made progress towards commercialization initiatives.