Developing a drug to fight a deadly childhood parasite

Around the world, diarrheal diseases are responsible for one in 10 deaths of children under the age of 5. One of the leading causes is Cryptosporidium, a microscopic parasite that is typically transmitted through contaminated water and usually lives in the small intestine. Yet it doesn’t lend itself to easy laboratory investigation and, until recently, scientists have been flummoxed in their attempts to make progress toward finding a treatment.

But thanks to the efforts of a new professor at the School of Veterinary Medicine, this is beginning to change.

Boris Striepen, who joined Penn’s faculty in July after nearly two decades at the University of Georgia, has been making inroads of late into the study of Cryptosporidium, developing ways to grow the organism, manipulate it, and test its susceptibility to drugs. The progress is much needed to make a dent in diarrheal disease.

“For rotavirus, there are good vaccines, and for some bacterial diseases, there are antibiotics,” Striepen says. “But for Cryptosporidium, there are no vaccines and only one FDA-approved drug that gives a modest benefit and is of very little use for those patients in biggest need, like young malnourished children or people with HIV/AIDS.”

Striepen’s advances in this area have only come in the last couple of years. Up until then, he had been working primarily on another parasite, Toxoplasma gondii, which is much more amenable to laboratory study.

Cryptosporidium was really an intractable organism,” Striepen says. “So for about 10 years, I had maybe one or two people in my lab working on that. They would be working alongside students doing interesting things with Toxo, who had something fluorescent that moves and would be knocking out three genes in a row, and the other students couldn’t even grow their organism. They were probably wondering, ‘Why am I saddled with this thing?’”

Around 2011, it became clear that Cryptosporidium was a major previously unappreciated cause of childhood illness, the Gates Foundation began devoting resources to researchers studying the parasite, including Striepen. This new support along with funding from the National Institutes of Health and the Wellcome Trust allowed him to take on riskier, more ambitious projects.

The breakthrough came toward the end of 2015, when he and his colleagues realized they could use CRISPR-Cas-9 technology to genetically manipulate Cryptosporidium. Striepen’s group created a method to evaluate disease severity that relies on the reporter molecule luciferase—the same protein that makes fireflies glow—and developed a mouse model that more closely recapitulates human disease than previous models.

In a paper in Nature published this summer, Striepen’s team, in collaboration with the Novartis Institute for Tropical Diseases, harnessed these advances, to perform a drug screening campaign that revealed the first candidate drug for this disease, KDU731, a member of a class of drugs known as pyrazolopyridines.

The drug remains to be tested in humans, but Striepen is hopeful that, working with new collaborators at Penn and elsewhere, this will be the first of many translational discoveries to assist children suffering from the downward spiral of malnutrition and parasite infection.

“Last year, I had the chance to visit with colleagues at a hospital in the capital of Zambia that treats malnourished kids,” he says. “That was a difficult place to visit. Along with tuberculosis, and HIV, cryptosporidiosis was a key threat to the life of these children.

“We are in need of drugs and vaccines that would help in particular in that environment.”