Detoxification Depot for b-amyloid peptides

b-淀粉样肽解毒库

• 批准号: 6934918
• 负责人: PAZHANI SUNDARAM
• 金额: $ 38.48万
• 依托单位: RECOMBINANT TECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6934918
• 关键词: Alzheimer' s disease; aminoacid analyzer; amyloid proteins; binding proteins; biomaterial evaluation; disease /disorder prevention /control; enzyme linked immunosorbent assay; gel; immunocytochemistry; laboratory mouse; nervous system disorder therapy; neuritic plaques; neurotoxicology; nonhuman therapy evaluation; postmortem; protein localization; protein transport; synthetic peptide

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.

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-β 肽可以穿过血脑屏障。我们的长期目标是开发一种有效的阿尔茨海默病疗法，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，从而阻止大脑中斑块的沉积。在第一阶段研究中，我们开发并展示了一种包含逆反肽的专有排毒凝胶，其作用就像一个“水槽”，在体外吸收 AB 肽。不可逆捕获的 AB 量和速率（体外 2 小时内 10 ug/100ul 凝胶）可用于在人体中产生下沉效应。现在，我们在二期提案中提出了一种更有效、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排毒库之外，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。本质上，含有由与聚合物连接的Abeta结合元件组成的缀合物的溶液与交联剂混合。该溶液可以皮下注射，它将迅速变成固体水凝胶。将评估排毒库降低大脑中 A-β 肽有毒聚集物水平的能力。几种版本的捕获肽将被包含在排毒凝胶中，并在 AD 小鼠中测试其功效。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者。对大鼠、兔子和狗进行的水凝胶安全性研究表明没有毒性。我们拥有“知识产权”，并提出商业化计划，以便与制药公司合作进行未来的评估。我们已经在商业化举措方面取得了进展。