A new RNA startup looks to reimagine heart treatments, with eyes set on Entresto
When Samir Ounzian left London a decade ago to study a little-understood branch of the genome at a Swiss lab, he wasn’t sure what he would find. Known as long-non-coding RNA, these sections were translated into looping rings of RNA — hence the name — but didn’t actually translate into proteins, and no one was quite sure how many there were or precisely what they were doing.
“We didn’t expect anything at the time,” Ounzian told Endpoints News, “because we didn’t really understand how frequent they were in the genome.”
Over the years, though, Ounzain and his collaborators found these strands expressed everywhere, including in one area they found particularly promising: the heart. In 2017, they showed in Science Translation Medicine that one such loop, called Wisper, controls fibrosis — scarring — in the heart after injury, and set about finding a way to drug it.
On Tuesday, the company Ounzain built around the approach, Haya Therapeutics, announced $20 million in seed funding led by Broadview Ventures, a cardiovascular-focused VC. They’ll use the proceeds to try to push an antisense therapy to neutralize Wisper strands into the clinic in 2 to 3 years, while also identifying other long-coding RNAs to drug throughout the body.
Long-non-coding RNAs are important, researchers now believe, in part because they govern how the same genes are expressed in different tissues, including how those genes respond to the environment. In the heart, Wisper turns on fibrosis in response to some type of trigger. Evolutionary, that was likely an advantage, helping protect the tissue from injury, Ounzain said. But now people are exposed to all sorts of damage — diabetes, high blood pressure, clogged arteries — that fibrosis only worsens.
“These new stresses of our species make the heart think it’s constantly stressed, and then the fibrosis just continues over time,” he said.
Although a series of heart failure drugs have hit the market over the last decade, most notably Novartis’s Entresto and Merck’s Verquvo, but none directly treat fibrosis. By shutting down Wisper, Ounzain believes they can not only stop fibrosis but reverse existing damage; scar tissue in the heart turns over quickly, he said, so if you stop the scarring process, eventually the tissue will restore itself.
They plan to first test the therapy in a rare form of heart failure called non-obstructive hypertrophic cardiomyopathy, where fibrosis levels are linked to symptom severity. If they get proof-of-concept there, they’ll move to heart failure with preserved ejection fraction — a common condition involving scarring in the heart and where there are so few options, the FDA approved Entresto for it, despite a failed pivotal trial.
Ounzain, though, doesn’t want Haya thought of as a heart company. They can do much more going after long-coding RNAs, he said.
“We believe this paradigm is more than the heart,” he said. “And we actually think it could be a very powerful paradigm for the future of anti-fibrotic drug development.”