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A forgotten scourge

The world’s neglected tropical diseases debilitate or kill more than one billion people worldwide. But there is hope as a small number of researchers in Canada and elsewhere join the battle to reduce the heavy burden of illness.

By DIANA SWIFT | DEC 06 2010
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They have strange names, such as yaws, Dumdum fever, river blindness and schistosomiasis. Others, like leprosy, are more familiar. What they have in common is this: they all belong to a group called neglected tropical diseases, or NTDs – chronic infectious conditions that together cause serious disability and developmental deficits in more than one billion people, mainly the world’s poorest of the poor. Collectively, NTDs rank sixth in the top 10 global causes of life-years lost to disability and premature death.

Endemic to Africa, Asia, Latin America and the Pacific Islands, they are also present in the southern Mediterranean and Middle East. The infections are caused by a range of bacteria, viruses, worms and protozoan parasites. They’re called neglected because they get little attention in developed countries, where they either don’t exist or, like leprosy, have long since been eradicated. Some are treatable; others as yet have no cure.

Often they overlap with other NTDs or with one or more of the lethal Big Three – HIV/AIDS, malaria and tuberculosis – with which they collaborate to swamp the immune system and spur premature death. Although they cost developing countries untold amounts in reduced quality of life and lost productivity, the dollars allocated to eradicating the diseases are minuscule compared with the number of people affected.

“There is little incentive for pharmaceutical companies to develop new, cheap and easy-to-administer treatments,” says Carlos Morillo, a cardiologist, NTD researcher and professor of medicine at McMaster University.

But now there is hope. In Canada and other developed countries, a small but growing number of researchers are working to control, if not eradicate, these infections. Despite sparse funding, researchers are motivated by the sheer numbers of very poor people whose childhoods are blighted and life spans shortened by NTDs.

Moreover, Western governments and pharmaceutical companies alike are becoming more sensitive to their responsibility to provide affordable medicines. In the past decade, global health groups have come together to plan strategic action and major drug makers have committed to donating drugs or supporting research to eliminate these scourges.

“Serious global research awareness about NTDs really dates only from about the late 1990s. There was research going on as far back as the 1960s, but NTDs were not really on the general radar, and there wasn’t much money for research,” says Kishor Wasan, a professor of pharmaceutical sciences at the University of British Columbia.

Dr. Wasan cites two turning points that swivelled the spotlight over to NTDs: “One, Doctors Without Borders won the Nobel Peace Prize in 1999 for their incredible work behind the scenes in this area. And two, the Bill & Melinda Gates Foundation was established in 2000.”

In the past decade or so, many academic centres have established research programs in global diseases. UBC’s Neglected Global Diseases Initiative is one such example. Its funding comes from a variety of sources, including the Canadian Institutes of Health Research, the World Health Organization and various philanthropic foundations. In fact, the emerging phenomenon could be termed “Pharmaceuticals Without Borders” for the move in developed countries to design and deliver medicines to underserved populations in the Third World.

In this milieu of heightened global awareness, Dr. Wasan is working on a cheap oral form of the drug Amphotericin B to target visceral leishmaniasis (or VL, known colloquially as Dumdum or black fever). Caused by tiny single-cell protozoan parasites transmitted by the female sand fly, VL is the second-largest parasitic killer in the world after malaria and strikes an estimated 500,000 people annually. In its less serious forms, it appears as a skin or mucous-membrane infection, but the parasites often migrate to vital organs such as the liver, spleen, lymph nodes and bone marrow. Left untreated, it can cause death.

Traditional treatment is based on the heavy metal antimony, which is cheap and effective but has toxic side effects. Amphotericin B therapy is currently given intravenously – with all the attendant costs of sterile clinic conditions, needles, IV bags and technical personnel. A cheap oral form would greatly facilitate treatment.

“The new product has been signed on to UBC’s Global Access Initiative, which supports wider access to medicines and better delivery systems,” says Dr. Wasan, who holds the CIHR/iCo Therapeutics Research Chair in Drug Delivery for Neglected Global Diseases.

The U.S. Food and Drug Administration recently granted Amphotericin B “orphan drug” status, a designation usually given to drugs that treat conditions affecting small numbers of people. In this case, it’s for a condition that affects very large numbers of poor people. Orphan designation qualifies the applicant for tax and marketing incentives, including tax credits for clinical research, exemption from application-filing fees, funding for clinical trials and seven years of market exclusivity after approval.

“The FDA’s recognition,” says Dr. Wasan, “is a huge step in allowing us to develop a cost-effective treatment for this disease. We are going to make this drug available at or below cost.”

On the other side of the country, molecular biologist Barbara Papadopoulou of Université Laval is also investigating VL, but from a different perspective.

“We are looking more at the parasite itself than the host. [The parasite] is very clever at dampening the function of immune cells,” says Dr. Papadopoulou, acting director of the infectious disease and immunology section of the Centre hospitalier universitaire de Québec (CHUQ) Research Centre. “If you can answer questions about the survival of the parasite,” she goes on, “you are in a good position to devise new therapeutic strategies.”

Dr. Papadopoulou admits to being fascinated by the amazing biology of these parasites and the complexity of the diseases they cause. “Discovering more about how these organisms adapt and survive under extremely harsh environments in different hosts is a source of inspiration – and a good lesson in life,” she observes. Another motivation for her is the critical need to improve the quality of life for the millions of infected people, especially young children whose growth and development are stunted by parasitic disease.

Recently, her group discovered an important mechanism that regulates several genes in the parasite. “In the end, we hope to develop a multi-target drug because this mechanism affects a lot of different genes, so the chances of success in eliminating the parasite are multiplied.” As for a vaccine, she says, “There is some hope, but it is not easy to get funding for vaccine research. Still, we could design a vaccine because we know a lot about the immunological response to the parasite.”

Despite the difficulty in getting funding, Robert Anderson’s primary goal is developing vaccines. A professor of microbiology and immunology at Dalhousie University, he’s zeroing in on the viruses that cause dengue fever and dengue hemorrhagic fever, two painful mosquito-borne infections with an estimated 50 million cases worldwide, more than two billion people at risk and no treatment. With financial support from CIHR, Dr. Anderson is studying viral proteins that disrupt the function of blood platelets and lead to hemorrhagic disease. The goal is to understand the body’s immunological responses to the virus with a view to developing a preventive vaccine.

But he, too, concedes that adequate research funding is a problem. “Sadly, governments and funding organizations often realize the importance of research only when there is a major health crisis – witness SARS and the H1N1 flu.”

Another parasite-driven NTD is Chagas disease. It affects at least nine million people – perhaps as many as 13 million – and poses a risk to 100 million, mainly in Latin America. The disease is transmitted in the feces of bugs that live in the walls of poorly constructed housing; it causes gastrointestinal problems and serious cardiac damage, leading to enlarged heart, arrhythmias, heart failure, stroke and sudden cardiac death. “It involves a very high burden of disease. People are very sick and there is a very rapid progression,” says McMaster’s Dr. Morillo.

He is a lead investigator in a 50-centre Latin American trial that challenges the conventional thinking that anti-parasitic drugs are useful only in the acute phase of the infection and not once heart damage is present. New research has shown that active parasites continue to promote the disease even in the chronic stage, says Dr. Morillo. “Our trial is testing the hypothesis that treating patients who already have early cardiomyopathy has some benefit,” he says.

In Montreal, another dedicated researcher is Brian Ward, chief of the infectious diseases division at the McGill University Health Centre. He’s using new technology to identify diagnostic and prognostic indicators for a number of NTDs, including Chagas disease, dengue fever and a serious flatworm-transmitted infection called schistosomiasis that can damage vital organs like the liver. “In many countries, especially Egypt, huge numbers are co-infected with hepatitis C and schistosomiasis, and this combination dramatically accelerates liver damage,” says Dr. Ward.

For many NTDs, the diagnostic and prognostic tests are poor. “With parasitic diseases, you are often still positive for the disease even after treatment,” explains Dr. Ward. “We can treat Chagas, or leishmania or sleeping sickness, but we have no idea if we’ve cured them.” So his group is looking for tests that will definitively indicate whether patients have been cured, have relapsed or been re-infected, and whether the disease is progressing. Such tests could spare patients unnecessary toxic therapies.

Ultimately, researchers in the industrialized world hope to transfer the development and delivery of essential medicines to the countries affected. But for now, the burden still lies with us. “We have to do the job since most of the endemic countries can’t afford to,” says Dr. Papadopoulou of Laval. “It has to be done in developed countries that have the money, personnel and infrastructure, then slowly transferred to the developing nations so they can take over.”

And, despite increased global awareness and support, things are proceeding too slowly for those on the research barricades. “There’s a lot of attention and a lot of buzzwords surrounding global diseases now, but they are still neglected in that the number of dollars going into research as a function of the number of people affected is far too small,” says Dr. Wasan.

Dr. Ward, meanwhile, remains frustrated that such a large share of the money is allocated to malaria, HIV/AIDS and tuberculosis – the Big Three. “Hundreds of millions go into these diseases when a small proportion of that could solve some of the next 12,” he laments. “Without for a moment minimizing the magnitude of the threat posed by HIV,” he says, “the Canadian HIV vaccine initiative has grabbed millions of dollars with little to no chance of making a substantive contribution to the development of a vaccine.”

Why? “Probably because it is far sexier for a government minister to stand up and say, ‘We’re going after an HIV vaccine’ than to say, ‘We’re saving lives through the prevention of intestinal parasites.’”

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Student activists target NTDs

On university campuses around the world, students are joining forces to help fight global diseases. The University Alliance for Essential Medicines is a student group with chapters across Canada and the U.S. and a growing number of chapters in Europe, Africa and Latin America. Its mission is three-fold:

  • addressing access to essential medicines through university drug-licensing policies
  • increasing biomedical research in neglected diseases
  • empowering students to play a role in improving access and innovation in health care.

“It was actually a bunch of student activists who opened my eyes to the potential of the anti-fungal drug Amphotericin B for treating visceral leishmaniasis,” says University of British Columbia researcher Kishor Wasan. The parasitic disease affects about half a million people a year. “I was developing [the drug] to treat fungal co-infections for people with AIDS right here in Vancouver, but it became clear that this drug could help millions of people in poor parts of the world.”

Malaria, the mass killer

Malaria, one of the Big Three global diseases, strikes 600 million people a year and kills one to three million. It’s not considered a neglected condition, but the single-cell, mosquito-born parasites that cause it are becoming resistant to drugs.

“There’s an urgent need for a new approach that targets new systems,” says John Dalton, a Canada Research Chair in Infectious Diseases at the Institute of Parasitology at McGill University.

His research targets the aminopeptidase enzyme in red blood cells. Malaria parasites in the blood use it to break down the hemoglobin into constituent amino acids to nourish their growth. One compound that inhibits the enzyme is bestatin, a fungus-based antibiotic that also fights cancer cells. Dr. Dalton is working with U.S. and Australian colleagues to design anti-enzyme chemicals that are more potent than bestatin and have characteristics that work well in pharmaceuticals, including being able to be taken orally, being well absorbed in the intestines and staying in the circulation.

Contagious: the growing global movements against NTDs

1999/ Doctors Without Borders sets up a fund to fight NTDs with the proceeds of its Nobel
Peace Prize.

2000/ The WHO launches a global program to eliminate lymphatic filariasis; Bill and Melinda Gates create their foundation.

2004/ Third global meeting of the Partners for Parasite Control.

2005/ First International Conference on the Control of Neglected Zoonotic Diseases is held; WHO Department of Control of Neglected Tropical Diseases is established.

2006/ Collaboration begins between WHO and the Foundation for Innovative New Diagnostics to develop and evaluate new diagnostic tests for human African sleeping sickness.

2007/ Global partners’ meeting on neglected tropical diseases is held at WHO headquarters.

2008/ The U.S. launches the Neglected Tropical Disease Initiative.

2010/ Several large pharmaceutical companies announce commitments to donate drugs or support WHO programs to eradicate NTDs ranging from Buruli ulcer and Chagas disease to leprosy and leishmaniasis.

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