Washington University School of Medicine in St. Louis has received a five-year, $13 million grant from the Bill & Melinda Gates Foundation to improve efforts to eliminate two parasitic diseases, elephantiasis and river blindness. These diseases belong to a group of infections known as neglected tropical diseases, which collectively have a health impact comparable to HIV and malaria.
"This project will work to optimize treatments that already are being used to help hundreds of millions of people," says principal investigator Gary Weil, M.D., professor of medicine and of molecular microbiology at the School of Medicine. "We have simple and cost-effective treatments for many neglected tropical diseases, and for a cost of about 50 cents per person we can alleviate a tremendous amount of human suffering and disability and potentially eliminate some of these diseases permanently."
The new project is informally called “Death to Onchocerciasis and Lymphatic Filariasis” (DOLF), after its two primary targets. It is believed to be the largest global health grant so far to the university.
According to the World Health Organization, lymphatic filariasis, caused by tiny worms spread by mosquito bites, is a leading cause of disability worldwide, infecting an estimated 120 million people and causing symptoms in 40 million. Weil says that as many as 1.3 billion people in 81 nations are at risk of infection with the parasites, which can live and reproduce for several years inside the human body and cause the disfiguring and disabling leg swelling known as elephantiasis.
A related worm, Onchocerca volvulus, causes onchocerciasis, also known as river blindness. It is spread by black fly bites and occurs mainly in Africa, where it infects an estimated 20 million people and has caused blindness in approximately 300,000.
Weil has been active for years in efforts to eliminate lymphatic filariasis via mass drug administration (MDA), an approach that gives antifilarial drugs to everyone in areas with high infection rates. Filarial worms need a critical mass of infected humans to spread effectively. MDA programs aim to reduce infection rates below that level to interrupt transmission. Organizers of the global MDA campaign, currently under way or completed in more than 50 nations, hope to eliminate the disease worldwide by 2020.
One of DOLF's three primary objectives, headed by Peter Fischer, D.Sc., visiting associate professor of medicine at the School of Medicine, will test the costs and benefits of twice-yearly mass drug administration versus the current standard annual treatment.
"Medicines for mass drug administration programs are donated by pharmaceutical companies such as GlaxoSmithKline and Merck, and those donations will be among the costs we will weigh against the benefits of more frequent treatment," Weil says. "If the twice-yearly dosing eliminates lymphatic filariasis more quickly, the added costs early on may be more than offset by savings later."
Weil expects the first objective's outcomes to depend heavily on localized variables such as culture, cooperation and environment. This may mean that the best dosing frequency will vary from country to country.
He and other project scientists haven't finalized the selection of countries that will participate in this objective, but they plan to include two regions in equatorial Africa where persons with lymphatic filariasis may also be infected with another filarial worm called Loa loa. MDA programs have not been possible in these regions previously because drugs used to treat lymphatic filariasis can cause life-threatening complications in people with heavy Loa infections.
Recent studies have shown that treating patients with a drug known as albendazole can safely treat filariasis in patients who also have Loa infections. DOLF scientists will see if mass drug administration with albendazole can lower infection rates enough to eliminate lymphatic filariasis in equatorial Africa where Loa loa is endemic.
DOLF's second objective will conduct two clinical trials of different treatments for lymphatic filariasis and one trial of new treatments for onchocerciasis. The trials will be subcontracted to scientists at Case Western Reserve University School of Medicine.
"This objective will take existing drugs and give them in different doses and combinations to see if they're more effective than the current treatments," Weil says. "For example, we will be testing whether two drugs, albendazole and ivermectin, can improve treatment for onchocerciasis if we give the drugs at higher doses and on a more frequent dosing schedule."
Research has shown that ivermectin mass drug administration, currently in use in approximately 33 countries, can eliminate onchocerciasis from infected regions, but it takes an estimated 10 to 15 years of mass treatments to clear the parasite. Project organizers hope the changes in dosing that they are testing will significantly reduce that time.
Weil calls the DOLF project's third objective, led by scientists at Michigan State University and McGill University, "teaching an old drug new tricks." The objective will focus on flubendazole, a drug originally developed in the 1970s that had excellent activity against filarial worms when it was given by injection in animals and humans. The oral drug is currently used to treat intestinal worm infections in domestic animals and humans.
Flubendazole might be a potent tool for treatment of lymphatic filariasis, but injections cause severe local reactions in some humans, and the current formulation of the oral drug is poorly absorbed and does not have much effect beyond the digestive system.
"There are now new ways to improve drug solubility and absorption," Weil says. "The DOLF project will review all available information on flubendazole and develop a plan for reformulating the drug for use against human filarial infections.”
Weil and his colleagues at Washington University conduct basic and applied research on worm parasites. They have developed important new diagnostic tests for filarial infections and conducted field research on disease elimination.
"I'm very excited," Weil says. "This new project will provide us with a chance to conduct high-impact research that should benefit the many people who suffer from these diseases."
Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.