Reawakening Heart’s Cells by Targeting Non-Coding RNA

A new study from Scripps Research shows that it may be possible to heal damaged heart tissue with medication by targeting an essential biomolecule that surges in failing heart muscle.

In a study published Monday in Nature Chemistry, the team shared their discovery compounds able to restart cellular production of a factor called VEGF-A in cellular models. Research has shown that VEGF-A acts as a signal to stem cells, causing them to rebuild blood vessels and muscle in damaged heart tissue, and improve blood flow.

"During a heart attack, the injury causes proteins that could promote new, healthy blood vessel growth to go silent," principal investigator Matthew Disney explains. "We analyzed the entire pathway for how the protein is silenced, and then we used that information to identify how to reinvigorate its expression." 

Disney and his team analyzed the genomics underlying VEGF-A production to assess optimal RNA drug targets, in collaboration with scientists at AstraZeneca. They focused on a microRNA precursor called pre-miR-377, finding it acts like a dimmer switch for VEGF-A production in failing heart muscle.

They then used computational and chemical tools in conjunction with a diverse set of compounds from AstraZeneca's collection to search for chemical partners able to selectively bind to the key conserved structural features of pre-miR-377.

"We delivered a lead small molecule compound to reprogram the cell's software to force it to re-express VEGF-A," Disney says. "Transforming TGP-377 into a potential medicine that reaches patients will take considerably more time and research. There are potential RNA drug targets for nearly every disease. We now have a much greater toolbox to search for lead molecules with medicinal potential."