RNA drug and antidote presage therapies of the future.
Researchers have found a new anticlotting agent and designed an antidote to fit it1. Their technique could turn up reversible drugs for other conditions.
Blood clots can trigger heart attacks and strokes. They are "the most frequent cause of illness and death in developed countries", says Edward Tuddenham of Imperial College of Science, Technology and Medicine, based at Hammersmith Hospital in London, UK.
Most clot-controlling drugs have serious drawbacks. Heparin and its antidote, used during and after surgery, respectively, can often cause adverse reactions. The dosage of another common blood-thinning drug, warfarin, is difficult to regulate, and it has no antidote.
The promising new drug and antidote are aptamers - short lengths of RNA that twist into blobs according to their chemical sequence and bind to molecules. Scientists at Duke University Medical Center in Durham, North Carolina, and colleagues screened one trillion aptamers for the ability to block certain proteins crucial to the blood clotting process. "We're essentially screening for shapes," says team member Bruce Sullenger.
Once they had chosen their clot-stopping aptamer, they built its antidote: another length of RNA with a complementary sequence. This second RNA snippet sticks to the first, disabling it. "It's a way to rationally design a regulated drug," says Christopher Rusconi, also of the Duke team.
In the test tube, different amounts of antidote either regulate or reverse the aptamer's anticlotting ability. Studies in animals are now underway.
"It's still early days," says Andrew Ellington, who studies aptamers at the University of Texas in Austin. He cautions that aptamers' drug potential has been studied for ten years and that none have been licensed, although some are almost there.
The demonstration that aptamers lead to their own antidotes is a major boost for their use as drugs. "It could be possible to do things you couldn't even contemplate with other drugs," says Ellington.
Drugs that must be delivered in bespoke doses, such as anaesthetics, chemotherapy and treatments for children and the elderly, could be made from aptamer-antidote pairs. Such double acts might even allow physicians to halt the effects of drugs in the event of adverse reactions or a misdiagnosis, says Sullenger: "It's like having the ability to recall that e-mail that you inadvertently sent."
Rusconi, C. P. et. al. RNA aptamers as reversible antagonists of coagulation factor IXa. Nature, 419, 90 - 94, (2002).