Breathing Room

Photo By Diane Williams | (Left) Nerve cell and the Neuromuscular Junction (NMJ) where the neurotransmitter acetylcholine triggers a muscle contraction through the exchange of sodium (Na) and potassium (K) across muscle fibers. Voltage-gated potassium and calcium channels on the nerve cell regulate the amount of acetylcholine in the NMJ. The greater the calcium influx into the nerve cell, the more acetylcholine is available at the NMJ for muscle contraction. Exposure to botulism neurotoxins causes paralysis by blocking the release of acetylcholine from the nerve terminal. (Right) 3,4-DAPP blocks voltage-gated potassium channels, allowing calcium channels to remain open for a longer period and increasing the probability of releasing more acetylcholine. (DTRA JSTO image)  

FT. BELVOIR, VA, UNITED STATES

04.24.2024

Courtesy Story

Defense Threat Reduction Agency's Chemical and Biological Technologies Department

A fast-acting, broad-spectrum therapeutic can treat the Joint Force after exposure to one of the most dangerous neurotoxins.

A new, fast-acting treatment is being developed for botulism—an intoxication caused by botulinum neurotoxin (BoNT) and one of the deadliest biological substances known. BoNT is a serious threat to the Joint Force through exposure to any of numerous BoNT toxin-producing environmental bacteria that contaminate food or infect battle wounds. BoNT can be inhaled if aerosolized during an explosion into contaminated soil or during an intentional attack.

BoNTs act by blocking the release of acetylcholine, the principal neurotransmitter at the neuromuscular junction (NMJ), resulting in muscle weakness that rapidly progresses to paralysis. Within 12 to 72 hours after exposure, BoNT causes symptoms such as blurred vision, drooping eyelids, difficulty in swallowing, talking, or breathing, and muscle weakness. Weakened or paralyzed muscles involved in breathing, primarily the diaphragm, can cause respiratory distress and death. Depending on the BoNT dose, muscle paralysis can last from weeks to months until BoNT is degraded or excreted, and nerve damage heals in the paralyzed muscles.

In the United States, botulism patients experiencing difficulty in breathing or respiratory distress are treated promptly using a forced oxygen mask or assisted mechanical ventilation with intravenous nutritional supplements, as needed, for long periods.

The Defense Threat Reduction Agency’s (DTRA) Chemical and Biological Technologies Department in its role as the Joint Science and Technology Office (JSTO) for Chemical and Biological Defense, an integral component of the Chemical and Biological Defense Program, collaborated with researchers at the U.S. Army Medical Research Institute of Chemical Defense (USAMRICD), Battelle Memorial Institute, the Southwest Research Institute, Wake Forest University, MRI Global, Aclairo Pharmaceutical Development Group, Inc., and manufacturer Catalyst Pharmaceuticals to develop an FDA-approved, small-molecule therapeutic called 3,4-Diaminopyridine Phosphate (3,4 DAPP) that can be administered to patients for a quick recovery from BoNT-induced paralysis at the NMJ.

Presently, the only FDA-approved treatment for adult botulism is a horse polyclonal hyperimmune serum named Botulism Antitoxin Heptavalent (HBAT). HBAT binds circulating BoNT like a sponge preventing it from getting into organ cells, where HBAT does not penetrate. This limits the window after exposure when HBAT can be effective since it is unable to act on BoNT that entered neurons, where the toxin acts. A neuron-penetrating therapy is needed to delay or mitigate the harm caused by BoNT.

Studies at USAMRICD screened current FDA-approved, small-molecule inhibitors that could potentially reverse BoNT-induced paralysis and focused on 3,4-DAPP based on its mechanism of action. To regulate the opening and closing of calcium channels, 3,4-DAPP blocks potassium channels on the nerve cell, prolonging the time that calcium channels remain open, which allows for an influx calcium into the nerve cell that reverses BoNT A serotype (BoTN/A)-induced paralysis.

The collaborative research group endeavors to generate sufficient safety, toxicity, and BoNT/A efficacy data to file an Investigational New Drug application with the FDA and conduct Phase I clinical safety trials. With the success of the studies invested in by DTRA JSTO, the Joint Program Executive Office for Chemical and Biological Defense will support the continued development of 3,4-DAPP for BoNT/A, including seeking new drug approval with the FDA for treating botulism.

It could be that 3,4-DAPP will be the first FDA-approved, fast-acting, small-molecule drug for the treatment of botulism. As 3,4-DAPP is broad spectrum in nature, it represents a potential therapeutic for many chemical or biological threats to the Joint Force that reduces respiratory drive, such as the synthetic opioids fentanyl and carfentanil, and biological toxins that reduce neuromuscular transmission. Continued studies with 3,4-DAPP against these agents will help researchers to understand the full broad-spectrum potential of this repurposed drug to treat chemical and biological threats and protect our warfighters, nation, and allies.

POC: Katherine Brittingham, Ph.D., [e-mail]

• Date Taken: 04.24.2024
• Date Posted: 04.24.2024 16:51
• Story ID: 469436
• Location: FT. BELVOIR, VA, US