Getting drugs into the brain is difficult. Maybe a parasite can do the job



While critics doubt that the parasitic villain could ever be transformed into a helpful hero, some researchers are intrigued by the idea.

Microbes like bacteria and parasites are usually seen as the bad guys, says Sara Molinari, a synthetic bacterial biologist at the University of Maryland in College Park, who was not involved in the work. But microbes have evolved “quite sophisticated relationships with our bodies,” she says. “The idea that we can leverage this relationship to guide them to do good things for us is really innovative.”

The challenge of crossing the blood-brain barrier

Current methods of delivering therapies to the brain often produce unpredictable results or have difficulty penetrating the protective shield known as the blood-brain barrier, says Shahar Bracha, a bioengineer and neuroscientist at MIT.SN: 5/2/23).

As a graduate student at Tel Aviv University, Bracha was looking for a better way to deliver therapeutic drugs and proteins to the brain. They include proteins that can replace missing or dysfunctional ones in people with degenerative and developmental genetic diseases that affect the nervous system, such as Parkinson’s disease and Rett syndrome.

Then she heard about T. gondii causing rats to behave recklessly. “It looks like that parasite has solved everything we need for drug delivery,” says Bracha.

The parasite, which humans can pick up from foods such as raw meat, uncooked shellfish, unwashed fruits and vegetables, as well as cat feces or contaminated soil, has evolved to cross the blood-brain barrier. Once there, it can infect brain cells and live silently inside them for a lifetime. It can also pump large proteins into the brain cells it affects without invading the cells themselves.

A ‘crazy idea’

Can T. gondii turn into a therapeutic tool?

“At first, it was like, ‘Oh, I wonder.’ Crazy idea,” says Bracha. “But the more I read about this idea, the more I could figure out an actual plan to test it.”

Bracha and colleagues in Israel joined him T. gondii researcher Lilach Sheiner at the University of Glasgow in Scotland to create a potentially useful version of the parasite.

When Anita Koshy, an infectious disease researcher at the University of Arizona College of Medicine in Tucson who studies T. gondiifirst heard someone float the idea of ​​the parasite as a therapy, she thought, “It’s a terrible idea. Who would agree to that?” But a few years later, when Sheiner approached her for advice, Koshy’s thinking had evolved and she accepted the project, she says.

If you take the long view and learn to “strip the risk” T. gondiithe parasite has several evolutionary aspects that make it attractive, she says.

Toxoplasma gondii The Risks

As parasites go, T. gondii it is already relatively safe for most people with healthy immune symptoms. About a quarter of healthy people worldwide have antibodies in their blood that indicate they have been infected T. gondii at some point. The US Centers for Disease Control and Prevention estimates that more than 40 million people in the United States carry the parasite.

But the parasite is not harmless. In the United States, it is a leading cause of death from foodborne illness and can damage the brain, eyes and other organs and cause hearing loss in people who develop severe disease.

Those with weakened immune systems have a higher risk of developing serious illnesses when exposed to them T. gondii. Pregnant women risk premature birth and pregnancy loss. In addition, the parasite can cause a number of problems for the baby, including blindness, hearing loss, epilepsy and jaundice. More than 200,000 cases of toxoplasmosis are diagnosed each year in the United States, with about 5,000 requiring hospitalization. About 750 people die every year from this disease.

Koshy’s previous research shows that brain cells that the parasite injects a payload of eventually die.

If researchers want to use the parasite to deliver drugs, they will need to learn how it causes disease and disable those mechanisms without harming it. T. gondiiits ability to silently infect the brain.

“That might be like trying to throw bazookas.”

Sebastian Lourido, parasitologist

Parasitologist Sebastian Lourido of the Whitehead Institute in Cambridge, Mass., says it may be impossible to T. gondii safe while maintaining all the qualities that would allow it to act as a cargo van. For example, the parasite gets inside immune cells and penetrates the blood-brain barrier, destroying those cells as it goes.

If the scientists disable it T. gondiiIts ability to kill cells and subvert the immune system means the parasite can never reach its destination to unload its payload. “It’s hard to imagine how you just project it away,” he says.

Construction of a delivery vehicle

As a first step, the team started by choosing two organelles T. gondii used to secrete its own proteins into host cells. An organelle, the rhoptry, is used to inject proteins into the brain cells the parasite infects, in an approach known as kiss-and-spit.

To deliver the proteins to the right place, the researchers had to write on them the molecular equivalent of an address. They did this by attaching the protein they wanted delivered to a protein the rhoptry was already releasing into the cells. Pig proteins were produced in the rhoptries, but the parasite did not secrete enough of the proteins into neurons grown in lab dishes for the researchers to detect.

This failure may be because the kiss-and-spit mechanism is too harsh for the fused proteins to survive, Lourido says. “That might be like trying to throw bazookas.”

The team also tinkered with dense granules, another type T. gondii organelle that secretes proteins once the parasite is safely inside the host cell. The researchers fused the proteins, including one called MeCP2, to a dense granule protein called GRA16. MeCP2 is mutated in people who have Rett syndrome, a genetic disorder involving seizures and developmental delays (SN: 9/3/21).

The parasite had no problem making MeCP2-GRA16 and unloading it into mammalian and human nerve cells and brain organoids grown in lab dishes.SN: 16.10.19).

The researchers also injected T. gondii parasites engineered to make MeCP2-GRA16 proteins in the stomach or blood of mice. From there, the parasites made their way to the rodents’ brains and began pumping the molten proteins into the brain cells. The mice had no symptoms, indicating that neither the infection nor the fusion protein triggered dangerous immune system reactions.

But the parasite is not sterilized. It could potentially still cause severe disease in humans, although Lourido notes that relatively few of the engineered parasites reached the brains of mice. It is common for engineered organisms to be weakened by researchers’ manipulations, says Molinari of the University of Maryland.

While the experiments were only a partial success, they were encouraging enough that some of the researchers formed an Israel-based company called Epeius Pharma to develop T. gondii as a protein delivery system. But Bracha and her colleagues point out that they are just taking the first steps toward turning the parasite into a vehicle and are nowhere near using it for medical treatments.

The team still has significant hurdles to overcome before the benefits of deliberately giving people a brain parasite can outweigh the risks, Koshy says. She is not involved with Epeius, but says her colleagues driving the research forward have “the kind of tenacity you need to take something that everyone says is going to fail and actually make it successful.”


#drugs #brain #difficult #parasite #job
Image Source : www.sciencenews.org

Leave a Comment

Your email address will not be published. Required fields are marked *

Scroll to Top