Project Number: 2030-42000-053-004-T
Project Type: Trust Fund Cooperative Agreement
Start Date: Apr 1, 2019
End Date: Mar 30, 2022
Currently therapy for botulism consists of intensive supportive care and treatment with equine-source antitoxin, called heptavalent botulinum antitoxin (HBAT). Botulinum antitoxin consists of equine-derived immunoglobulin G (IgG) antibodies directed against the antigenically distinct botulinum neurotoxins (BoNTs). These antibodies neutralize circulating neurotoxin molecules by coating the molecules not yet bound to nerve endings and preventing attachment to neurons. However, HBAT and antibodies do not reverse existing paralysis. Therefore, antibody-based therapies must be administered as early as possible after symptom onset. Previous research showed an approved drug, Bithionol, inhibits host caspases, including caspase-3 and -7, and also reduces the detrimental effects of BoNT/A in vivo. We evaluated the efficacy of Bithionol as a therapeutic agent during BoNT/A intoxication in the oral mouse bioassays and showed protection from intoxication symptoms. In this project, we will further confirm the efficacy of bithionol in the prevention of botulism from other botulinum neurotoxin serotypes as well as different treatment regiments. We will also evaluate the therapeutic range and pharmacokinetics of this drug. An effective therapeutic drug against botulism would greatly improve disease outcomes in cases of accidental or intentional contamination of the food supply.
To achieve the proposed objectives, we will: 1) Review literature on clinical and non-clinical drug safety; 2) Evaluate the efficacy of bithionol in vivo using the mouse oral models for different BoNT serotypes; 3) Determine the pharmacokinetics of drug in the mouse model.