New Strategy May Help Reverse Paralysis From The Worlds Most Deadly Toxin

Botulinum toxin neurotoxic protein. By StudioMolekuul/Shutterstock.com

Produced by anaerobic bacteria, botulinum toxin is one of the world's deadliest toxins. At most, it only takes 1 nanogram of the substance to kill a human due to its neurotoxic effects on the nervous system.

Although cases of human ingestion of the toxin are rare, cases normally occur when people consume food or drink containing the toxin, which is produced by the Clostridium botulinum bacteria normally found in soil or sea sediments. The bacterium itself is not toxic, but when starved of oxygen, it produces the botulinum toxin protein as a byproduct. It is this protein byproduct that is really toxic, and could very rapidly lead to paralysis as it infiltrates the nervous system, and ultimately could lead to death as patients are unable to breathe for themselves. 

Now, researchers have developed a novel proof of concept strategy that could counteract the devastating effects of botulinum toxin, with initial tests in animal models proven to be successful. If it works in humans, it could counteract the paralyzing effects of the toxin and may help prevent people that ingest the toxin from getting severely ill. 

“In a life-threatening situation, this will be very, very helpful,” Professor Brenda Anne Wilson, a toxin microbiologist at the University of Illinois, told Science Magazine

Two research teams – one led by Assistant Professor Konstantin Ichtchenko, a biochemist from the New York University School of Medicine, the other led by Assistant Professor Min Dong, a neuroscientist and microbiologist at Boston Childrens Hospital – have used a neat tactic to get antibodies (the signaling cues for the immune system to attack) to the place where they are required to counteract the toxin.

The researchers produced a modified version of the toxin that could help get antibodies into nerve cells, where the original botulinum toxin normally invades and escape detection by the immune system.

We basically just created a Trojan horse,” Ichtchenko commented.

Ichtchenko's team used genetic engineering techniques to make tweaks to the natural botulinum toxin protein, rendering the modified version less toxic and essentially creating a "Trojan Horse" that does not harm nerve cells to the same extent as the natural toxin. Dong, who headed the second research team, clarified the modified version of the toxin Ichtchenko's team created was still able to cause paralysis in animal models when administered at very high doses, but nevertheless, it remains a dose-dependent situation. 

Dong's team took a different approach. They developed a drug that essentially used parts of natural botulinum toxin that are toxic, and combined it with a related botulinum toxin that did not have the ability to invade and damage human nerve cells. The combined elements left Dong with a drug that was not toxic in mice, even at very high doses. 

Both Ichtchenko and Dong's teams then combined their modified toxin products to an engineered tiny antibody – derived from alpacas – that has the ability to neutralize the naturally occurring botulinum toxin protein once it reaches its target. The idea was to get the modified toxin products to guide the tiny antibodies into nerve cells. These tiny antibodies, referred to as nanobodies, are capable of being more effectively transported by a secondary player (in this case the modified toxins), and once they get to the target they can neutralize the natural botulinum toxin within these nerve cells, potentially alleviating some of the side effects. 

Following this, Dong's team then used this engineered antibody with their modified toxin attached in mice exposed to a lethal dose of naturally occurring botulinum toxin. The researchers injected mice with a lethal dose of the toxin, and then 9 hours later after the animals were already paralyzed provided their treatment option. The 10 animals given the highest dose of the drug were mobile again within 6 hours of receiving treatment. This was exciting, as it showed the cocktail compound containing the alpaca antibodies had therapeutic benefits. 

Following the findings in mice by Dong's team, Ichtchenko's team described positive results using their "Trojan Horse" approach in mice, guinea pigs, and monkeys in the same journal paper. The approach provided a safe and effective treatment against botulinum toxin, the team wrote in a significant paper

Patrick McNutt, PhD, of the Wake Forest Institute for Regenerative Medicine, who participated in the research, said in a statement, "This is one of those serendipitous moments in science where two groups, working independently, demonstrate similar results for a long-standing problem," McNutt also said. "We are currently modifying this drug to enhance its therapeutic properties against botulism and exploring whether the same approach can be repurposed to treat other neuronal diseases."

Both Ichtchenko and Dong are now continuing to refine their products and thereafter seek FDA approval. Once approved, trials in humans could begin. James Marks, a molecular biologist at the University of California, San Francisco, commented on the findings, written in Science Magazine: "Experimental drugs face a long, hard road” from animal results to an approved product, Marks said. But this is where it starts.”"

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