Wake Forest Institute for Regenerative Medicine (WFIRM) researchers are investigating a drug used to treat neuromuscular weakness as a potential treatment for botulism, a rare but serious disease.
Botulinum neurotoxins (BoNTs) are a family of bacterial poisons – the most poisonous substances known – responsible for the clinical disease known as botulism. These neurotoxins act within nerve terminals to destroy proteins necessary for muscle contraction, causing paralysis that develops into respiratory arrest and can lead to death. The Centers for Disease Control (CDC) considers botulinum neurotoxins a Tier 1 agent, posing the highest risk following accidental or deliberate misuse.
The deliberate misuse aspect of the toxin is what drives the WFIRM researchers and their work to find a treatment. Currently, the only specific treatment for botulism is early administration with antitoxin. However, antitoxin is only effective if administered before prior botulism symptoms are evident. Once symptoms emerge, three out of four patients require long-term artificial ventilation for survival.
“Despite decades of effort, there are no antidotes for the life-threatening consequences of botulism. This failure is primarily because the toxin hides within the nerve terminal, where it poses a challenging target for delivery of therapeutic molecules,” said corresponding author of the paper Patrick McNutt, PhD, who leads this research effort at WFIRM.
The researchers build on their previous work to show that administration of the FDA-approved drug 3,4-diaminopyridine (3,4-DAP) reverses botulism symptoms in a pre-clinical model. The drug is an approved treatment for Lambert Eaton Myasthenic Syndrome, an autoimmune disease caused by reduced acetylcholine release and neuromuscular weakness. Botulism paralysis is caused by reduction of acetylcholine release from motor nerve terminals to subthreshold levels required for muscle contraction.
Acetylcholine is the chief chemical messenger of the parasympathetic nervous system, the part of the autonomic nervous system that contracts smooth muscles, dilates blood vessels, and slows heart rate.
For this study, recently published in Molecular Medicine, the researchers developed a continuous 3,4-DAP infusion model and measured dose-dependent effects on toxic signs and survival after a lethal dose of botulinum neurotoxin. They found that continuous infusion with the drug produces rapid and sustained therapeutic benefits while survival requires continuous infusion for longer than four days.
“This is the first small-molecule therapy to directly reverse toxic signs and promote survival when administered post-symptomatically after a lethal dose of botulism,” said McNutt. “Our data supports the immediate clinical use of DAP in botulism patients.”
The authors declare no competing interests.
Additional co-authors include: James B Machamer, Edwin J Vazquez-Cintron, Sean W O’Brien, Kyle E Kelly, Amber C Altvater, Kathleen T Pagarigan, Parker B Dubee and Celinia A Ondeck.
This work was supported by the Defense Threat Reduction Agency—Joint Science and Technology Office (Grant Number CB10721) and the National Institute of Allergy and Infectious Diseases (AI093504). Funding agencies played no role in study design, data collection, data analysis, data interpretation or writing the manuscript. Views expressed in this article do not reflect the official policy of the Department of Army, Department of Defense or U.S. Government.
About the Wake Forest Institute for Regenerative Medicine: The Wake Forest Institute for Regenerative Medicine is recognized as an international leader in translating scientific discovery into clinical therapies, with many world firsts, including the development and implantation of the first engineered organ in a patient. Over 400 people at the institute, the largest in the world, work on more than 40 different tissues and organs. A number of the basic principles of tissue engineering and regenerative medicine were first developed at the institute. WFIRM researchers have successfully engineered replacement tissues and organs in all four categories – flat structures, tubular tissues, hollow organs and solid organs – and 15 different applications of cell/tissue therapy technologies, such as skin, urethras, cartilage, bladders, muscle, kidney, and vaginal organs, have been successfully used in human patients. The institute, which is part of Wake Forest School of Medicine, is located in the Innovation Quarter in downtown Winston-Salem, NC, and is driven by the urgent needs of patients. The institute is making a global difference in regenerative medicine through collaborations with over 400 entities and institutions worldwide, through its government, academic and industry partnerships, its start-up entities, and through major initiatives in breakthrough technologies, such as tissue engineering, cell therapies, diagnostics, drug discovery, biomanufacturing, nanotechnology, gene editing and 3D printing.