Researchers from UT Southwestern Medical Center and Australia have demonstrated the potential of using a test drug to cure malaria through a single effective dose. The study was recently published in Science Translational Medicine,which claims that the drug could be used for preventive treatment as well.
The project was funded by MMV, the Welch Foundation, the National Institutes of Health, and the Wellcome Trust.
The Present Scenario
Malaria is an extremely infectious disease. The malaria-causing parasite Plasmodium is transmitted by mosquito, resulting in the annual death of approximately 600,000 people worldwide. About 200 million cases are reported each year, of which most of the reported deaths are of children under the age of five living in sub-Saharan Africa. It is estimated that around 3 billion people are significantly at risk in 97 countries.
Presently, frontline treatments consist of ACTs (Artemisinin-based Combination Therapies) which have reduced the prevalence of malaria to quite an extent. Dr. Phillips, who holds the Beatrice and Miguel Elias Distinguished Chair in Biomedical Science and the Carolyn R. Bacon Professorship in Medical Science and Education. They pointed out that drug resistance is slowly becoming a problem, as seen in Thailand, Vietnam, Cambodia, Laos and Myanmar. He explained that the parasite had adapted very adequately to the drugs being used, and finding new medicines with long-lasting mechanisms of action was the only way to fight it.
Discovering The New Drug – DSM265
Work on the new drug started in Dr Philip’s lab, with during high-throughput tests at UT Southwestern’s core screening laboratory. In 2008, her research team discovered a compound that inhibited the enzyme dihydroorotate dehydrogenase (DHODH), which is vital for the survival of the malaria parasite. This enzyme facilitates the replication and proliferation of the parasite during infections.
Along with senior author Dr. Susan Charman from Monash University, Dr. Pradipsinh Rathod at the University of Washington and not-for-profit Medicines for Malaria Venture (MMV) affiliated researchers, the compound that inhibited DHODH was refined to prepare the lead drug DSM265. The latter is the first DHODH inhibitor to enter clinical developmental stages as a potential treatment for malaria.
How DSM265 Works
DSM265 inhibits the replication and spread of malaria parasites in the blood and liver, henceforth killing the drug-resistant Plasmodium. It does this by targeting the ability of the parasite to manufacture nucleotide precursors required for DNA and RNA synthesis. Researchers also observed that the drug was well-tolerated and effectual in preclinical models.
“DSM265 could be among the first single-dose cures for malaria, and would be used in partnership with another drug to combat drug-resistance,” stated lead author Dr. Margaret Phillips, Professor of Pharmacology at UT Southwestern. “The drug could also be developed as a once-weekly preventive for people travelling to malaria-endemic regions and for those with compromised immunity living in areas susceptible to seasonal infections.”
Even though these scenarios may take several years to come into actual practice, depending on the outcome of present and future clinical trials, but researchers seem optimistic. Trials with preclinical models showed the drug to be well-tolerated in non-human subjects. These tests helped scientists estimate the optimal dose and extent of effectiveness of the drug for humans.
The first clinical trial – a safety study – was conducted in Australia, followed by an ongoing study on drug efficiency in Peru by MMV researchers. More clinical trials have been planned, including a test to determine the usefulness of DSM265 as a preventive drug. UT Southwestern is facilitating as an advisory body and is providing support with biomarker assays.
Drs. Phillips, Charman, Rathod, and Dr. Jeremy Burrows of MMV have been named as the inventors of DSM265 in a pending patent application covering the drug and related compounds. The drug has been licensed to MMV, which works with institutions and drug companies around the world, supporting research and development of new malaria treatments. DSM265 is one of several anti-malarial drugs now in various stages of development, in collaboration with MMV.