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.

Public Health Relevance

Botulinum neurotoxins (BoNTs) are the most toxic substances known to mankind, and yet an important medicine for neuromuscular disorders and a wide range of other diseases. The trafficking and tissue distributions of BoNT, however, have not been studied due to their extremely high toxicity. This project aims to use a detoxified recombinant BoNT to examine BoNT trafficking and distributions with mouse whole body imaging. Results from this project will have important impact on understanding the toxicity of BoNT to design countermeasures, and will create better understanding of their medical applications as well as potential side effects in their medical uses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Research Grants (R03)
Project #
1R03AI103868-01A1
Application #
8584036
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Ranallo, Ryan
Project Start
2013-05-23
Project End
2015-04-30
Budget Start
2013-05-23
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$77,166
Indirect Cost
$27,166
Name
University of Massachusetts Dartmouth
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
799477427
City
North Dartmouth
State
MA
Country
United States
Zip Code
02747
Ravichandran, Easwaran; Janardhanan, Pavithra; Patel, Kruti et al. (2016) In Vivo Toxicity and Immunological Characterization of Detoxified Recombinant Botulinum Neurotoxin Type A. Pharm Res 33:639-52
Kumar, Raj; Dhaliwal, Harkiran Preet; Kukreja, Roshan Vijay et al. (2016) The Botulinum Toxin as a Therapeutic Agent: Molecular Structure and Mechanism of Action in Motor and Sensory Systems. Semin Neurol 36:10-9
Chellappan, Gowri; Kumar, Raj; Santos, Erin et al. (2015) Structural and functional analysis of botulinum neurotoxin subunits for pH-dependent membrane channel formation and translocation. Biochim Biophys Acta 1854:1510-6
Chellappan, Gowri; Kumar, Raj; Cai, Shuowei et al. (2014) Role of neurotoxin associated proteins in the low pH induced structural changes in the botulinum neurotoxin complex. Protein J 33:557-64