Detoxification Depot for b-amyloid peptides

描述(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，由淀粉样前体蛋白的两个重叠片段(AB1-40和AB1-42)聚集形成。这些A-β多肽可以穿过血脑屏障。我们的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AB(β淀粉样蛋白)多肽，从而阻止斑块在大脑中的沉积。在第一阶段的研究中，我们在体外开发并展示了一种包含逆转录多肽的前体解毒凝胶，该多肽的作用类似于吸引AB多肽的“水槽”。不可逆捕获AB的量和速率(体外2小时内10ug/100ul凝胶)可用于在人体内产生下沉效应。在我们的第二阶段提案中，我们现在提出了一种更有效、更特异和更方便的治疗系统。除了使用我们在第一阶段建立的毒库外，我们还计划改进AB捕获水凝胶配方，并在AD小鼠模型中评估其体内性能。基本上，包含由连接到聚合物的Aβ结合元件组成的结合物的溶液与交联剂混合。这种溶液可以注射到皮下，在那里它会迅速变成固体水凝胶。将评估毒物库降低大脑中A-β多肽毒性聚集体水平的能力。几个版本的捕获肽将被包括在解毒凝胶中，并在AD小鼠身上进行有效性测试。评估参数将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对象。在大鼠、兔子和狗身上进行的水凝胶安全性研究表明，该水凝胶没有毒性。我们拥有‘知识产权’的权利，并提出了一项商业化计划，以便与一家制药公司合作进行未来的评估。我们已经在商业化倡议方面取得了进展。

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.