Botulinum Neurotoxin Trafficking and Tissue Distribution with Mouse Body Imaging

描述（由申请人提供）：肉毒神经毒素（BoNT）被疾病控制中心（CDC）列为A类生物恐怖主义制剂，是人类已知的毒性最大的物质。同时，BoNT也被用作针对许多神经肌肉疾病以及美容疾病的有效治疗剂。在其天然形式中，BoNT以复杂形式分泌，由150 kDa神经毒素和一组神经毒素相关蛋白（NAP）组成，这些蛋白保护毒素免受胃肠道中的低pH和蛋白酶的影响。事实上，目前所有的治疗产品都是复杂的形式。最近在临床应用中使用BoNT的增长，以及FDA对其黑盒标签的指定，保证了对毒素从其施用部位到各种组织和器官的运动的更深入的理解。此外，实时获取和传播信息对于在发生食物中毒和故意接触生物恐怖主义或战区发生大规模毁灭性武器袭击的情况下制定适当的干预措施至关重要。我们建议在小鼠模型体内建立BoNT的处置，在使用生物成像技术和A型BoNT（BoNT/A）的无毒替代物通过各种进入途径给药后。我们计划解决几个关键的问题有关的剂量，路线，和贩运率，并将检查效用的系统，用于评估在不同组织中的分布的毒性。在该拟议的初步研究结束时，我们预期已经建立了替代分子（drBoNT/A），用于通过不同途径（口服、ip、鼻内等）给药后BoNT/A摄取、运输、组织分布和消除途径的可视化。从这种系统的操作中获得的信息将与针对肉毒中毒的医学干预、治疗应用时毒素的潜在扩散以及drBoNT/A作为不同组织中神经的潜在药物递送载体的有效使用相关。

DESCRIPTION (provided by applicant): Botulinum neurotoxins (BoNTs), classified as category A bioterrorism agent(s) by the Centers for Disease Control (CDC), are the most toxic substances known to mankind. At the same time BoNTs are also used as effective therapeutics against numerous neuro-muscular disorders as well as for aesthetic purposes'. In its native form, BoNTs are secreted in complex forms, consisting of the 150 kDa neurotoxin and a group of neurotoxin-associated proteins (NAPs) which protect the toxin against low pH and proteases in the GI tract. Virtually all the current therapeutic products are in the complex form. Recent growth in the use of BoNTs for clinical applications, and its black box label designation by FDA, warrants a more in depth understanding of the toxin's movement from the site of its administration to various tissues and organs. Moreover, real-time uptake and trafficking information is essential to devise adequate interventions in case of food poisoning and intentional exposure cases of bioterrorism or a WMD attack in war theater. We propose to establish disposition of BoNTs within the body of a mouse model, after administering it through various routes of entry using bio-imaging technology and a non-toxic surrogate of type A BoNT (BoNT/A). We plan to address several critical questions relevant to dose, route, and rate of trafficking; and will also examine utility of the system for assessing the distribution of the toxi in different tissues. At the end of this proposed pilot study, we expect to have established a surrogate molecule (drBoNT/A) for visualization of BoNT/A uptake, trafficking, tissue distribution, and elimination routes after administration by different routes (oral, ip, intranasal etc.). The information derived from operation of such a system will be relevant to medical intervention against botulism, potential diffusion of the toxin upon therapeutic application, and t effective use of the drBoNT/A as a potential drug delivery vehicle to nerves in different tissues.