Physical Address

304 North Cardinal St.
Dorchester Center, MA 02124

Possible new treatment identified for neglected tropical disease


The last time a new drug for Chagas disease was introduced, Richard Nixon was in his first term as U.S. president. Now, in a study published yesterday, researchers unveil a drug that appears to safely eliminate from mice and monkeys the parasites that cause the sometimes-fatal tropical disease. The scientists hope clinical trials of the compound can begin soon and that it will have fewer side effects than the current Chagas treatments.

The study is “very impressive” and provides enough evidence to support human testing, says medical epidemiologist Caryn Bern of the University of California, San Francisco, who wasn’t connected to the research.

The culprit in Chagas disease is the sinuous microscopic parasite Trypanosoma cruzi. People usually become infected when they are bitten by insects known as kissing bugs, which harbor the parasites, but the disease can spread in several other ways, including through food and drinks that contain the insects or their feces. Most of the more than 6 million people infected with T. cruzi live in Latin America. However, Chagas disease has become a problem in other countries as well because of infected people emigrating around the world from Latin America. In a study published in July, for instance, Bern and her colleagues estimated about 288,000 people in the United States are carrying the parasites.

Although T. cruzi won’t kill most of these people, the parasites bore into organs such as the heart and large intestine and can lurk there for decades, causing tissue damage. Up to 30% of infected people eventually suffer heart problems, including abnormal cardiac rhythms and heart failure.

The two approved drugs for treating the illness, benznidazole and nifurtimox, are more than 50 years old. “They are not awful,” but their drawbacks discourage people from using them, says immunoparasitologist Rick Tarleton of the University of Georgia. The drugs don’t always work, trigger side effects such as nerve damage and rashes, and have to be taken for 60 straight days. Although four other potential treatments for Chagas disease reached clinical trials in the past decade, they proved toxic or were less effective than the current drugs.

To create the new compound, Tarleton and colleagues teamed up with researchers from Anacor Pharmaceuticals, a Palo Alto, California–based company that had been screening compounds against a variety of parasites. After several rounds of testing and improving the most promising molecules, the scientists came up with a candidate they dubbed AN15368 that seemed to eliminate T. cruzi from infected mice. Even when the researchers suppressed the mice’s immune systems, the parasites did not reappear, bolstering the case that the drug had eradicated the interlopers. Unlike current Chagas disease drugs, the compound thwarts a step—the fine-tuning of newly made messenger RNA molecules—necessary for the parasite to synthesize proteins.  

Tarleton says most efforts to develop new drugs for Chagas disease have jumped from mouse results to tests in people, where the drugs stumbled. “The large number of clinical trial failures based on that approach tells you something is missing.” So, the scientists decided to also evaluate AN15368in monkeys, which they hoped would better predict the drug’s effectiveness in humans.

They took advantage of natural T. cruzi infections at a monkey research facility outside Austin, Texas, that allows the animals outdoors. As the monkeys groom each other, they eat the kissing bugs they find—and pick up the parasites, which are widespread in the insects in the United States. After treating 19 infected monkeys with AN15368 for 60 days, the researchers could no longer detect the parasites in blood from any of the animals, they report in Nature Microbiology. Tissue samples from a variety of organs in nine of the treated animals were also negative for T. cruzi.

Not only did all of the monkeys recover, but the scientists detected no side effects in the animals. The researchers have followed some of the 19 treated monkeys for more than 3 years, Tarleton says, and blood tests continue to indicate the drug purged the parasites from the animals. “It’s not a guarantee, but it bodes well” that the drug will also prove effective in people, he says. The researchers need to perform further animal tests on the drug’s safety, likely in rodents and monkeys, Tarleton says. After that work is complete, he and his colleagues hope to license the compound to an undisclosed company that will perform a clinical trial.

Cardiologist Carlos Morillo of the University of Calgary describes the results as “a breakthrough.” The drugs that failed Chagas clinical trials in the past few years were “refurbished” treatments for other diseases, he notes, and belong to the same chemical family. But AN15368 uses “a different mechanism than the other drugs we have, which is important,” Morillo says.

The results are “very promising,” says Jadel Kratz, an R&D manager for the Drugs for Neglected Diseases initiative in São Paulo. Testing the drug in nonhuman primates and tracking the animals for so long strengthens the findings, he says. Still, Kratz cautions that the compound has to pass through the drug development “valley of death,” the animal studies and initial clinical trials that will determine whether it is safe.

Bern hopes that future work will show a shorter course of AN15368 can eliminate the parasites. To deliver a better Chagas treatment, she says, “60 days is too long.”



Source link

Leave a Reply

Your email address will not be published.