Scientists genetically modified a tiny, worm-like parasite to produce a life-saving antitoxin from inside the living host.
In first study of its kind, researchers modify hookworm Ancylostoma ceylanicum so that it produces antibodies that partially neutralize the powerful pufferfish venom tetrodotoxin.
This approach has so far been tested in hamsters, but the ultimate aim is to use it in people. In fact, the study was funded by the U.S. Department of Defense with the aim of developing protective treatments for military personnel exposed to chemical or biological hazards such as tetrodotoxin, said the study’s co-authors. alex lucasthe director of the Australian Institute of Tropical Health and Medicine at James Cook University told Live Science.
In future work, these insects could be engineered to produce a variety of other drugs and excrete them inside the human body, the study’s authors wrote in a report published June 3. nature communication. For example, they may provide long-term treatment for chronic diseases such as type 2 diabetes Or inflammatory bowel syndrome, Lucas suggested.
From parasite to antitoxin factory
Hookworms are one of humanity’s oldest parasites and infect upward 400 million people globallyMainly in tropical areas. Like internal leeches, these small intestinal worms stick to the inner wall of the intestine to feed on blood, while also releasing a variety of anti-inflammatory and immunosuppressive compounds to prevent them from being expelled from the body.
Each worm is about 0.4 inches (1 centimeter) long and drinks less than two drops of blood a day, and healthy hosts often do not experience any symptoms of infection. The hookworm used in this study, A. ceylanicum, Infects humans, dogs and cats.
“Hookworms have spent millions of years perfecting how to ensure long-term survival inside a human host and how to get molecules out of their body and into ours,” said the study’s co-author. Makedonka MitrevaThe professor at Washington University School of Medicine in St. Louis, Missouri, said in a statement.
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The cocktail of compounds produced by these parasites has already shown some promise. treatment of metabolic disorders such as metabolic syndrome and type 2 diabetes, as well celiac disease. However, studies to date have been limited to molecules naturally produced by hookworms.
The new work takes this concept one step further. “We asked: What if we could add another molecule to the approximately 1,000 things the worm already secretes that is therapeutically useful to people?” Mitreva said. “This study shows that it’s not just a concept. It works.”
You might also consider the possibility of a wormer that produces very small amounts of food allergen to desensitize the host to childhood food allergies.
Alex Lucas, director of the Australian Institute of Tropical Health and Medicine at James Cook University
using the crisper In a gene-editing technique, the team inserted a gene coding for an antibody known to counteract the deadly pufferfish venom tetrodotoxin into the genome of hookworms at the egg stage. Mitreva’s team had to carefully consider the location of the gene, ensuring that it did not interfere with other important regions of the DNA, yet still promote the production and secretion of the new protein.
The team then infected hamsters with 80 to 100 modified parasite larvae. Upon maturing, the adult worms with the newly inserted gene were able to produce the antibody and then secrete it into the hamster’s bloodstream. Blood samples taken from infected hamsters later partially neutralized the tetrodotoxin poison in laboratory experiments, showing that the compounds produced by the worms were active in hamsters.
On paper, the same approach could be used to secrete other antibodies or peptide drugs – which are small pieces of protein – to directly treat gastrointestinal disorders, Lucas said.
“We’re actively thinking about introducing antibodies that neutralize inflammatory hormones or cytokines,” he said, “to treat conditions such as inflammatory bowel disease.” “You can also think about the possibility of a worm that produces very small amounts of food allergen to desensitize the host to childhood food allergies,” he said.
Looking ahead, the team wants to increase the durability of the therapeutic molecules released by the insects, since they can only make so much at a time, he said.
Although it may seem odd to infect a person with a parasite to make them feel better, hookworm actually has an excellent safety profile, Lucas said. The quirks of their biology mean that there is no chance of an infection getting out of control.
Hookworm larvae enter the body through the skin and move to the small intestine where they mature into adults, often living for years without affecting the host. Any eggs produced by adult parasites must hatch from outside the host; They are passed out in the host’s feces. This means that the number of adult worms in the body remains fairly constant.
Additionally, with a single dose of standard deworming treatment, the infection is cured within 24 hours. Therefore any hookworm-based treatment can be easily cleared from a person’s system.
“This is exciting and it’s really opening up a whole new way to deliver and produce therapeutic molecules,” Lucas said.