|How Genomics Propelled a Malaria Drug to Clinical Trials|
By Kate Ruder
This is the story of how the genome of the malaria parasite helped scientists identify a potential drug to treat malaria and then start clinical trials in Africa, all in record time. Often the benefits of sequencing the genomes of deadly human pathogens are not immediately clear, but malaria may be an important exception.
The story begins in 1997, when scientists began sequencing the genome of the most deadly malaria parasite, Plasmodium falciparum, and posted preliminary DNA sequences in an online database.
Meanwhile, a group of researchers in Germany had a hunch that they might kill the parasite by inhibiting essential genes. They already knew the genes in bacteria so they searched the parasite database online for similar genes—and bingo, they found them!
Then they looked for a drug that would shut the genes down and had another stroke of good luck.
They found that an antibiotic drug called fosmidomycin that had been developed by a Japanese company in the 1970s, appeared to inhibit the proteins that these genes made. The company no longer manufactured the drug, but the researchers were able to produce it from scratch themselves in the laboratory.
The advantage of the “new” drug is that it had already been shown to be safe as an antibiotic in patients in clinical trials in the ‘70s, even though its antimalarial potential was not realized. This cut out years of development and safety testing typically needed to bring a new drug to clinical trials.
In 1999, the German group published research in Science showing that the drug inhibits the growth of malaria parasites in the laboratory and that it cures mice infected with a rodent form of malaria.
It was a breakthrough in genomics. Here were scientists publishing discoveries and research on new antimalarials before the genome was even completed.
In October 2002, researchers in Rockville, Maryland, Palo Alto, California, and the United Kingdom published the sequence of the entire malaria parasite genome.
In a study in the West African nation of Gabon in 2002, the drug showed promise. It seemed to help roughly 80 percent of patients infected with malaria, but the parasites inside the patients rebounded in a few days. The researchers had by now teamed up with other scientists in Germany and Gabon.
So, the researchers combined the drug with clindomycin, a commonly used antibiotic that keeps the parasite at bay over time. Clinical trials of the combination treatment were completed this year in Gabon. The two drugs worked well together and were well tolerated in patients, according to the scientists, who will publish their findings next year.
Researchers say they are ready for the next phase of trials, but their lack of funds may jeopardize the future of the new treatment. The European Union and German Ministry of Research funded the original trials.
The advantage of fosmidomycin is that it targets the malaria parasite in different ways than another other drugs currently in use, which could be a tremendous advantage in treating patients infected with multi-drug resistant strains. In Gabon, and in many parts of the world, resistance to the widely used drug chloroquine is widespread.
Fosmidomycin, the only drug in clinical development that belongs to a new class of antimalarial drugs, acts through a novel but well-understood mechanism, says Hassan Jomaa of Justus-Liebig-Universitat in Giessan, Germany.
Peter Kremsner of the University of Tübingen in Germany, who has led the drug trials in Gabon, says the application of fosmidomycin is the “best example” of the application of genomes to human medicine.
Jomaa, who made the original discovery, is quick to point out that the genome sequence alone did not guarantee that they would find a good drug target. The key, he says, was knowing which specific genes to look for in the parasite and then comparing the parasite genome sequences to the genomes of bacteria.
He emphasizes that just comparing two related genomes does not yield new drug targets.
“This was comparative genomics, but it was based on a very clear idea. We did not go in blind,” Jomaa says. It was a mixture of suspecting a good target, finding that target, and having a drug that was already established in the clinic.
“It was a nice combination, but there was also a lot of luck. We know that lots of groups aren’t so lucky,” he says.
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