Researchers are studying a drug used for neuromuscular weakness as a possible treatment for botulism

Researchers are studying a drug used for neuromuscular weakness as a possible treatment for botulism

Researchers at the Wake Forest Institute for Regenerative Medicine (WFIRM) are studying a drug used to treat neuromuscular weakness as a possible treatment for botulism, a rare but serious disease.

Botulinum neurotoxins (BoNTs) are a family of bacterial toxins – the most toxic substances known – that are responsible for the disease known as botulism. These neurotoxins act in nerve endings to destroy proteins necessary for muscle contraction, causing paralysis that progresses to respiratory failure and can lead to death. The Centers for Disease Control (CDC) considers botulinum neurotoxins to be a Level 1 agent, which poses the highest risk following accidental or intentional abuse.

The conscious abuse aspect of the toxin drives WFIRM researchers and their work to find a treatment. Currently, the only specific treatment for botulism is early administration of an antitoxin. However, antitoxin is only effective if administered before previous botulism symptoms are apparent. Once symptoms appear, three out of four patients require long-term mechanical ventilation to survive.

"Despite decades of effort, there is no antidote for the life-threatening consequences of botulism. This failure is largely due to the toxin hiding in the nerve ending, where it represents 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 are building on their previous work to show that administration of the FDA-approved drug 3,4-diaminopyridine (3,4-DAP) reverses botulism symptoms in a preclinical model. The drug is an approved treatment for Lambert-Eaton myasthenic syndrome, an autoimmune disorder caused by decreased release of acetylcholine and neuromuscular weakness. Botulism paralysis is caused by the reduction of acetylcholine release from motor nerve endings to subthreshold levels required for muscle contraction.

Acetylcholine is the primary 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, researchers developed a continuous 3,4-DAP infusion model and measured dose-dependent effects on toxic signs and survival following a lethal dose of botulinum neurotoxin. They found that continuous infusion of the drug provides rapid and sustained therapeutic benefits, while survival requires continuous infusion for more than four days.

This is the first small molecule therapy to directly reverse toxic signs and promote survival when administered postsymptomatically after a lethal dose of botulism. Our data support the immediate clinical use of DAP in botulism patients.”

Patrick McNutt, PhD, corresponding author of the article

Source:

Atrium Health Wake Forest Baptist

Reference:

Machamer, J.B., et al. (2022) Antidote treatment of botulism in rats by continuous infusion with 3,4-diaminopyridine. Molecular medicine. doi.org/10.1186/s10020-022-00487-4.