Novel Intracellular Therapeutic Agent for Botulinum Intoxication

描述（由申请人提供）：生物防御毒素，如蓖麻毒素、肉毒杆菌神经毒素和志贺毒素，由于其高毒性和有限的暴露后治疗选择，是恐怖袭击的关注来源。每一种蛋白质毒素都表现出一种酶活性，这是其毒性的基础。吸入和摄入是蛋白质毒素进入的主要途径，一旦这些分子进入细胞，治疗选择就受到严重限制。物理科学公司（PSI）提议开发高度特异性的结合剂，以抑制肉毒杆菌神经毒素（BoNT）的催化活性。提出的新疗法将包括有效递送药物到靶细胞细胞质的材料和方法，从而逆转神经递质释放的抑制。I期研究将开发新型BoNT抑制剂，并通过体外和细胞试验证明其有效性。在第二阶段，将对药物和运载工具进行优化，并在活体动物模型中测试它们预防或逆转BoNT中毒影响的能力。我们预计，该系统将向细胞质输送足够数量的治疗药物，使药物的LD50增加至少10倍，并显著缩短BoNT暴露的恢复时间。公共卫生相关性：蓖麻毒素和肉毒杆菌等蛋白毒素暴露后的治疗选择有限。本研究旨在开发蛋白质毒素暴露后的治疗方法，这将大大提高生存率。

DESCRIPTION (provided by applicant): Biodefense toxins such as ricin, botulinum neurotoxins, and Shiga toxin are a source of concern for terrorist attacks due to their high toxicity and the limited post-exposure treatment alternatives. Each of these protein toxins exhibits an enzymatic activity that is the basis of its toxicity. Inhalation and ingestion are the primary routes of entry for protein toxins, and once these molecules have entered the cell, treatment options are severely limited. Physical Sciences Inc. (PSI) proposes to develop highly specific binding agents that will inhibit the catalytic activity of botulinum neurotoxins (BoNT). The proposed novel therapeutics will incorporate materials and methods for efficient delivery of the agents to the cytoplasm of target cells thus reversing inhibition of neurotransmitter release. Phase I research will develop novel BoNT inhibitors and demonstrate their efficacy using both in vitro and cell-based assays. In Phase II the agents and delivery vehicles will be optimized and will be tested for their ability to prevent or reverse the effects of BoNT intoxication in live animal models. We anticipate that the proposed system will deliver sufficient quantities of therapeutic to the cytoplasm to increase the LD50 of the agents at least 10-fold and significantly reduce recovery time for BoNT exposure. PUBLIC HEALTH RELEVANCE: Post-exposure treatment options for protein toxins such as ricin and botulinum are limited. This research seeks to develop post-exposure therapies for protein toxin exposure that will greatly improve survival rates.