A bloodstream scavenger which sweeps up the debris of damaged cells might stop the formation of deadly blood clots without triggering an equally threatening bleed.
The compound – PAMAM G-3 – may be the first in a new class of drugs aimed at addressing this difficult challenge. Researchers from Duke University Medical Centre report that PAMAM G-3 – a nucleic acid-binding polymer (NABP) – prevents activation of the process that leads to the formation of dangerous blood clots while avoiding factors essential to normal clot formation.
“In the thrombosis (clotting) space, the holy grail has been to make something anti-thrombotic that doesn’t significantly increase your chance of haemorrhage or bleeding,” said Bruce A Sullenger, senior author of the study published in Proceedings of the National Academy of Sciences.
“We think this is a promising example of a type of compound that could do that. If it can be clinically developed and exhibit the same properties in humans, clearly that would improve safety and outcome of treating patients who have thrombotic disease.”
Dying and diseased cells spill rogue bits of DNA and RNA into the bloodstream at high levels. This activates an inflammatory immune response, which also triggers the coagulation response. Previous research has shown that NABPs have potent anti-inflammatory properties and have the potential to interrupt the inflammatory response that underpins autoimmune disorders like multiple sclerosis and lupus.
Test-tube based assays and experiments in two mouse models of thrombosis showed that NABPs were potent inhibitors of thrombosis, but importantly also didn’t trigger abnormal bleeding. After screening several NABPs, PAMAM G-3 was found to be the most effective thanks to its anticoagulant potency and low toxicity.
In further work, researchers hope to better understand how the nucleic acids and phosphates are mediating the coagulation response, and will engineer additional NABP compounds to improve potency, safety and tolerability.
Proceedings of the National Academy of Sciences www.pnas.org