Chagas disease, leishmaniasis and sleeping sickness kill more than 50,000 people a year
A newly identified compound could help create more potent drugs against all three
At first look, three particular tropical diseases could seem unrelated.
They affect millions of people worldwide, but in much different ways. One can cause cardiac arrest in 30% of people infected, another can enter the brain to cause confusion and changes in behavior, and the last can cause skin lesions and swelling of the liver and spleen and can destroy the lining of your nose, mouth and throat.
These are the symptoms of Chagas disease, human African trypanosomiasis (also called sleeping sickness) and leishmaniasis, respectively. They’re part of a wider group of conditions known as neglected tropical diseases, and scientists are working on a type of drug that could treat all three – regardless of their differences.
Three become one
Each disease predominantly infects people in a different region of the world. Chagas affects populations in South America, African trypanosomiasis is mainly within Africa, and leishmaniasis infects across both continents, as well as Asia. Each is also spread by the bite of three very distinct insects: triatomine bugs, tsetse flies and sandflies.
But between them, these diseases infect 20 million people each year – and kill more than 50,000 – despite the available treatments. The drugs currently used to treat the diseases can have severe side effects, can require intravenous delivery in a hospital and need to be taken for a month or more, making them less than ideal in the poverty-stricken communities where the diseases occur.
“The drugs available are all very bad. They’re very toxic,” said Dr. Elmarie Myburgh of the University of York’s department of biology.
But a new study co-authored by Myburgh and published Monday found one compound that could be used to develop a type of drug to tackle all three diseases more potently, and with fewer side effects.
The parasites behind each of the diseases belong to a wider family of protozoa, known as kinetoplastids, and scientists at the University of York and pharmaceutical giant Novartis are targeting this group to develop more effective treatments.
“If you compare their genomes, you see a lot of similarities,” Myburgh said. “[But] it’s not easy to find something that kills all three of these parasites.”
Knowing that the diseases have this underlying biology in common, teams at the Genomics Institute of the Novartis Research Foundation screened more than 3 million compounds for their effect against each parasite in both mice and human cells. One, called GNF6702, not only killed all three, it didn’t cause any damage when applied to human cells – suggesting that there would be no side effects.
“You don’t want anything that can target the same thing in humans and kill human cells,” Myburgh said.
When her team tested the newly identified compound in infected mice, levels of the parasite became undetectable for all three diseases.
“It’s possible this could lead to a drug,” said professor Jeremy Mottram of York’s Department of Biology, another co-author on the study. But Mottram added that the next steps involved in turning the compound into a drug are numerous and challenging.
“A lot of research needs to be done to convert this compound into a drug against all three diseases,” he said. “But there is commitment.”
Mottram doesn’t believe one pill will be created against this group of diseases, largely because each disease attacks different parts of the body and will require a drug that can penetrate each region. For example, human African trypanosomiasis will need a drug that can enter the brain – an extremely complicated task – while a drug to fight leishmaniasis would need to enter the liver.
But the demand is high.
The need for treatment
According to the World Health Organization, about 6 million to 7 million people worldwide – mainly in Latin America – are infected with Trypanosoma cruzi, the parasite responsible for Chagas disease. By contrast, people infected with the Zika virus numbered fewer than 2,000 as of Thursday.
The drugs benznidazole and nifurtimox are currently used to treat patients with Chagas disease but have adverse side effects, cannot be taken by pregnant women or people with any history of psychiatric disorders, and must be taken for up to two months. They also must be taken soon after someone is infected for greater chances of success.
“A drug that acts quicker is ideal,” Mottram said.
As for the other diseases, the desire is to move away from IV drips to enable more treatment through oral pills. “In Africa, [an IV] is not very easy,” Myburgh said. As all three diseases tend to affect mostly poorer communities, access to hospitals and the option of staying in a hospital is not always feasible.
“You’re not going to treat the disease if you’re not using the right method,” Myburgh said.
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To make the new drugs a reality, there is pharmaceutical backup from Novartis, which is taking the compound through the next stages of drug development while testing other options.
“Many compounds fall out of the drug discovery process as you go,” said Richard Glynne, former executive director of genetics and neglected diseases at Novartis, who led the company’s involvement in the research. “We can’t say it’s this compound that could be a drug.” But his former team is determined to use it as the starting point to find the one that will.
“Cells and animals only approximate man, and we cannot accurately predict this effect will translate to man,” said Graeme Bilbe, research and development director at the nonprofit Drugs for Neglected Diseases initiative. He added that in addition to safety, the teams involved will need to determine the proper dosage as well as how the drug will enter the correct region of the body.
Bilbe agrees that one pill probably will not be the answer. Instead, he and Mottram think there will be three pills derived from one compound.
“Maybe for two diseases, this could be the case, as there are precedents, but usually, we would try to tailor-make a drug for each disease,” Bilbe said. “But at this stage, so far, so good.”
Either way, this approach to drug discovery – taking on multiple diseases at once – is more cost-effective.
Everyone in the field agrees on the need for new drugs. “In no way is there a great solution with the [drugs] currently available,” Glynne said.