Genetically modified hookworms produce and deliver therapeutics – WashU Medicine

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Hookworms, intestinal parasites that infect hundreds of millions of people in under-resourced tropical regions around the globe, have evolved to survive inside the human gut for years, secreting molecules that enable co-existence with their hosts. Now, researchers at Washington University School of Medicine in St. Louis have harnessed that biological mechanism for potential human benefit, engineering a hookworm to produce and deliver a drug within a living host.

In a new study, the team reports the first successful genetic modification of the human hookworm. It was designed to produce an antibody that neutralizes tetrodotoxin, a deadly neurotoxin produced by pufferfish and other marine animals. After colonizing an animal host with the modified hookworms, the parasites produced the antitoxin and secreted it into the bloodstream, partially inactivating the toxin.

The findings demonstrate that this drug production and delivery approach could be a long-term solution to any number of medical needs, from chronic conditions requiring continuous drug treatment to exposure to toxins in remote locations without medical care available.

The findings were published June 3 in Nature Communications.

“The hookworm has spent millions of years perfecting how to assure long-term survival inside a human host and how to get molecules out of its body and into ours,” said senior author Makedonka Mitreva, PhD, the Gordon R. Miller Professor in the John T. Milliken Department of Medicine’s Division of Infectious Diseases at WashU Medicine. “We asked: What if we could add one more molecule to the roughly 1,000 things the worm already secretes, something therapeutically useful to people? This study shows that’s not just a concept. It works.”

A parasite that delivers

Hookworms have already been studied as treatments for inflammatory bowel diseases such as ulcerative colitis, based on evidence that the anti-inflammatory molecules the worms secrete can dampen the immune responses that drive those conditions. Mitreva’s team set out to build on that foundation by engineering the worm to secrete a therapeutic of the researchers’ choosing, rather than relying solely on what the parasite produces naturally.

The appeal of hookworms as a long-term drug production and delivery platform stems from a quirk of their biology. When a person is infected with a controlled number of hookworm larvae, which can be administered orally as a pill or through the skin like a lotion, the worms migrate to the small intestine and take up residence, often for years. Because they cannot multiply inside the host, the number of worms stays fixed, and the infection remains controlled. If the infection ever needs to be cleared, a single dose of an oral anti-parasitic drug eliminates the hookworms within 24 hours.

Although natural hookworm infection may cause only mild digestive symptoms in healthy adults, chronic infection with large number of hookworms can be dangerous for children, pregnant people and malnourished or otherwise vulnerable individuals, leading to anemia, poor growth and development, pregnancy complications and, in extreme untreated cases, heart problems or death. This underscores the importance of keeping the infection strictly controlled for therapeutic use, Mitreva noted, which is possible because of the worms’ inability to reproduce without spending part of their life cycle in soil.

The antibody selected for this proof-of-concept study neutralizes tetrodotoxin, a paralyzing and potentially lethal toxin with no antidote. The work was funded by the U.S. government’s Defense Advanced Research Projects Agency, with an eye toward finding solutions to biological and chemical threats to soldiers in remote locations.

The project presented significant technical hurdles: gene-editing tools that work in other organisms had not been adapted for hookworms, and no one had previously achieved stable genetic modification in the species.

To adapt hookworms for therapeutic use, Mitreva and her team drew on more than two decades of hookworm genomics research conducted at WashU Medicine. This depth of data helped them understand the organism’s biology from the cellular to the genetic level, allowing them to locate a viable site in the genome to insert the new gene carrying instructions for making the new antitoxin. Critically, they had to ensure the insertion wouldn’t disrupt surrounding gene activity and...