Botulinum Neurotoxin Trafficking and Tissue Distribution with Mouse Body Imaging

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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.