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蛋白斑块，阿尔茨海默氏病（AD）的特征，是由淀粉样蛋白前体蛋白的2个重叠片段（AB1-40和AB1-42）聚集而形成的。这些A-β肽可以穿越血脑屏障。我们的长期目标是通过使用皮下水凝胶识别，浓缩和消除AB（β-淀粉样蛋白）肽，从而制定有效的阿尔茨海默氏病疗法，从而停止大脑中斑块的沉积。在第一阶段的研究中，我们开发并证明了一种过早的排毒凝胶，其中包含一种复古的肽，该肽的作用像是在体外吸引AB肽的“下水道”。可逆地捕获的AB的量和速率（在2小时内10 ug/100uul的凝胶体外）可用于产生人类的下水道效果。现在，我们在我们的II期建议中提出了一个更有效，更特定和方便的治疗系统。除了使用我们在第一阶段建立的排毒仓库外，我们计划在AD的鼠模型中改善AB捕获水凝胶配方并评估其性能。本质上，包含由Abeta结合元件组成的偶联物与聚合物相关的溶液与交联试剂混合。该溶液可以皮下注射，其中它将迅速成为固体水凝胶。将评估排毒仓库降低大脑中A-beta肽毒性聚集体水平的能力。排毒凝胶中将包括几种版本的捕获肽，并在AD小鼠中测试了功效。评估参数将包括免疫组织化学和生化测量。如果成功，该排毒仓库将成为人类使用的候选人。对在大鼠，兔子和狗中进行的水凝胶进行的安全研究表达了不毒性。我们拥有“知识产权”的权利，并提出了与制药公司合作进行未来评估的商业化计划。我们已经在商业化计划方面取得了进步。