JUPITER, Fla.—Dr. Matthew Disney, a research chemist and professor in the Department of Chemistry at the Scripps Research Institute’s Florida campus, began his career looking to defy skeptics. The structure and shape of human RNA fed the belief that it was essentially undruggable, but a drive to unlock the capability drove Disney from the inception of his work as a scientist.
And now that RNA focus might help fix broken hearts.
The Human Genome Project indicated that we produce more RNA than proteins and that non-coding RNAs were driving healthy and disease biology. Disney’s prolonged deep exploration of the three-dimensional structure of RNA found deep pockets there, and small molecules that bind to those pockets. While RNA had generally been thought to be undruggable, these binding small molecules presented a world of possibility.
In a new study conducted at Scripps Research Institute, Disney illustrates how that can be applied in response to specific disease molecules to help repair heart tissue damaged by heart attacks and heart disease with medication. With his team, he unlocked a pathway to restart a factor called VEGF-A, short for vascular endothelial growth factor A, that is known to improve blood flow and stimulate stem cells to rebuild blood vessels and muscle following a heart attack. VEGF-A is known to be suppressed in diseased hearts, hindering organ repair, but the Disney team found a solution.
Over time, Disney and Scripps developed an informatics database of small molecules known to bind with RNA. AstraZeneca approached the lab and challenged them to utilize Scripps’s database in conjunction with theirs to find a binder that would stimulate message RNA to create a key therapy to repair damaged heart tissue, specifically aiming for one that would increase VEGF. In several rounds of cross-computational models using computational and experimental models, they found a microRNA precursor called pre-miR-377 that acts like a dimmer switch for VEGF-A production in failing heart muscle. In fact, the search of the two databases increased the dataset of RNA binders by 20-fold.
“We could drug RNA by knowing which genes were dysregulated in a failing heart,” Disney explains. “We wanted to short-circuit that dysregulation to have a downstream pathway of increasing VEGF to repair the damage. Some RNAs will be overproduced to silence VEGF; if you can re-increase it, you can repair that damage. During a heart attack, the injury causes proteins that could promote new, healthy blood vessel growth to go silent. We analyzed the entire pathway for how the protein is silenced, and then we used that information to identify how to reinvigorate its expression.”
Their exploration found numerous hits to the target, while recognizing that there were “on” targets and “off” targets, and the team engineered a hybrid molecule that achieved a remarkable on-target specificity. While the compound has not yet been tested in animals, Scripps is seeking funding for the next steps, even with the likelihood that AstraZeneca and other pharmaceutical companies may have those studies underway.
“We delivered a lead small-molecule compound to reprogram the cell’s software to force it to re-express VEGF-A,” Disney says. “Transforming [it] into a potential medicine that reaches patients will take considerably more time and research.”
The very discovery of a large number of small-molecule materials that bind RNA with a very high affinity and selectivity creates opportunities for pharmaceutical companies to embark on medicinal computations to find more drug-like binders. Scripps published their findings ahead of animal testing, a rare instance where the magnitude of the discovery justified the early release. Their discovery could likely be used in other genetically defined diseases including amyotrophic lateral sclerosis, diabetic wound recovery and numerous cancers. This test case that demonstrates the real possibility of reliably and predictably targeting RNA, and promoting specific protein production bodes well for future advances.
“There are a lot of diseases where we know that RNA plays a role that is hard to drug at the protein level. 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. The hope for all of this basic science is that it gets translated into helping somebody,” concluded Disney.