DNA-based drug to prevent blood clots

Various medical circumstances, including heart attacks and extreme cases of COVID-19, necessitate the use of anticoagulants — medicines that prevent blood clots. But the most commonly used, heparin, can in some cases induce potentially fatal side effects by making the blood clots worse rather than better. Now Japanese researchers have proposed a side effect-free anticoagulating treatment that has so far proved effective in test mice and could be ready for human trials in just a few years.

Heparin was the first anticoagulant and is used widely, but a small number of recipients (up to 3%) suffer the side effect heparin-induced thrombocytopenia (HIT), a potentially fatal and rapid clotting of the blood and the opposite of the intended effect. Because of the low number of HIT sufferers and thus lack of interest from the pharmaceutical industry, this issue is underexplored, despite its severity and increase due to COVID-19. It can be especially problematic in pregnant women as they cannot take existing treatments due to those potentially adversely affecting the foetus.

“The best treatment for HIT is an infusion of what are called thrombin inhibitors, but current drugs can lead to severe bleeding and there is no antidote to avoid this,” said Associate Professor Keitaro Yoshimoto from The University of Tokyo. “Ideally, we could avoid HIT altogether. But at present, that is not possible, so we need a new low-risk thrombin inhibitor to replace current drugs. My team and I have created such an anticoagulant and have demonstrated it in mice and also in human blood plasma.”

Yoshimoto has a history in biochemistry and the science of molecular separation, specialising in a method called MACE-SELEX for the selection of aptamers, or short sections of DNA useful for medicine. He teamed up with Assistant Professor Asuka Sakata of Nara Medical University, who specialises in thrombosis biology. They decided to use Yoshimoto’s ideas to solve medical issues raised in Sakata’s research, with their results published in the journal Molecular Therapy Nucleic Acids.

Together with their colleagues, the researchers devised a next-generation thrombin inhibitor consisting of DNA molecules that includes a novel mechanism to prevent the severe bleeding. The key molecule in the drug is called a bispecific aptamer and its special feature is being able to bind to multiple things simultaneously. Another useful feature is short DNA sections which act as an antidote to the undesirable clotting side effect during HIT.

This DNA-based drug essentially enables more complex behaviours than drugs based on simpler, more traditional chemistry. From their studies in mice, the team has shown the treatment is around 10 times as effective as the current best treatments for HIT. An additional benefit to pregnant women is that the nucleic acid-based drug and accompanying antidote do not cross the placenta to the foetus, as the DNA molecules in the drug are too large to cross the barrier presented by the placenta.

“We hope to proceed with human trials soon,” Yoshimoto said. “It will take up to two years for preclinical studies and five years to complete clinical trials in humans. Though the number of HIT sufferers is small, it’s such a severe condition I feel it’s important we tackle it quickly.”

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