A new RNA therapy could help the heart repair itself

(Press-News.org) After a heart attack, cardiologists can reopen blocked vessels and restore blood flow, but the muscle cells that died will never be replaced

"The heart is one of the organs with the least ability to regenerate," said Ke Cheng, Alan L. Kaganov Professor of Biomedical Engineering at Columbia Engineering. "The spontaneous regeneration power is very, very limited."

In a study published March 5 in Science, Cheng and his colleagues describe a therapy designed to enhance the heart’s own ability to protect and repair itself after injury. Cheng’s innovation in drug delivery points to a future where RNA therapy allows the body to produce its own medicine targeted at specific organs. 

"You don't have to open the chest or send a wire to the heart to deliver this drug," Cheng said. "In principle, all the clinician needs to do is to inject the particles into the arm."

Study co-author Torsten Vahl, an attending physician at Columbia University Irving Medical Center/NewYork-Presbyterian Hospital and an assistant professor of medicine at Columbia’s Vagelos College of Physicians and Surgeons, sees an injection that can help the heart heal as an exciting step forward.

“As a clinician who opens up arteries with stents for patients who come to us with heart attacks, I am highly aware that we have a large unmet need for our patients,” Vahl said. “Too many times, they are left with severe heart damage that results later in heart failure.”

In lab experiments, a single injection significantly reduced scarring and improved heart function in small and large animals. Crucially, therapies based on RNA technology stand to be less expensive and more accessible than existing interventions, such as organ transplantation or stem cell therapies. 

What newborn hearts know During the first days of life, many mammals have a short-lived ability to regenerate heart muscle cells. A hormone called atrial natriuretic peptide (ANP) plays a key role by encouraging the growth of new blood vessels, calming inflammation, and reducing the formation of scars. As an individual ages, the amount of ANP in their bodies decreases substantially, and the regenerative capacity observed in newborn hearts largely disappears by adulthood. 

The team saw this effect in experiments that compared newborn and adult mice after a heart attack. In newborn hearts, the gene that produces ANP's precursor ramped up more than 25 times its normal level. In adult hearts, it rose only about 10 times, which might be insufficient to support meaningful regeneration. When the team experimentally blocked that gene, called Nppa, in newborn mice, the hearts lost much of their ability to heal. 

"The whole idea is that we learn from nature," Cheng said. "The neonatal heart spontaneously produces more of this molecule after a heart attack. That's probably why young hearts can regenerate themselves. The adult can't produce a sufficient amount, so we found a way to supplement this to the heart.”

Researchers have understood the potential of ANP for decades, but it’s difficult to use as a conventional drug because it begins breaking down after just a few minutes in the body. 

The muscle as an RNA drug factory Delivering a drug to the heart in a sustained and minimally invasive way is a significant challenge. Drugs aimed at organs such as the liver, lungs, or spleen can often accumulate naturally because of the unique features of their vascular systems and cellular uptake mechanisms. By contrast, the heart lacks such natural accumulation mechanisms, making efficient cardiac drug delivery more difficult. 

“Because of these challenges, researchers have worked on cardiac drug delivery with infusions directly into the blood vessels of the heart, injections into the heart muscle, and injections into the pericardium, which is the sac surrounding the heart,” Vahl said. “All of these methods are invasive and need to be performed in a cath lab.”

The team's solution was to stop trying to deliver the drug to the heart at all. Instead, they developed a two-phase approach that starts by creating a “prodrug” in skeletal muscle before transforming it into ANP within the heart itself. 

The researchers designed RNA-lipid nanoparticles that encode Nppa, causing muscle cells in the thigh or arm to produce a molecule called pro-ANP. This molecule, which is not reactive in the body, circulates through the entire bloodstream. A specific enzyme, called Corin, transforms it into ANP. Corin is roughly 60 times more common in the heart than in other organs. In other words, the drug circulates until it reaches the one organ equipped to activate it. 

“Targeting is based on a specific cleavage of an enzyme that is naturally expressed in the heart,” Cheng said. “The idea is that you don't have to touch the heart or open the chest. All you need to do is to inject the arm.” 

To keep production going long enough to help, the team used a specially designed self-amplifying RNA (saRNA) that replicates itself inside cells. The effects of a single injection lasted for at least four weeks. 

"The patient doesn't have to go to the hospital today and tomorrow," Cheng said. "They may only have to go once per month."

Looking ahead Before a therapy can move from animal studies to human trials, researchers typically need to show it works across different species with a range of conditions that reflect the real patient population, rather than young and healthy mice. Cheng's team ran the experiment in large animals, aged mice, in animals genetically prone to atherosclerosis, and in mice with diet-induced type 2 diabetes. They also tested what happens when treatment is delayed a week after the heart attack, by which point significant damage has already set in. The therapy worked consistently across all of them.

The team included more than a dozen of Cheng’s colleagues from the Department of Biomedical Engineering. Vahl and Lauren Sharan Ranard are affiliated with the Seymour, Paul and Gloria Milstein Division of Cardiology and the Structural Heart and Valve Center at CUIMC. Alexander Romanov is affiliated with the Institute of Comparative Medicine at Columbia University.

"We tested the drug in different disease comorbidities," Cheng said. "And we also tested delayed treatment. We hope that, even if a patient had a heart attack weeks before getting the drug, it’s still effective."

Beyond heart attacks, this saRNA delivery strategy stands to improve therapies for conditions including kidney disease, high blood pressure, and preeclampsia.

“Cell damage is a problem that not only affects the heart but many organs,” Vahl said. “If we can prove that this type of therapy can regenerate cardiac cells in the clinical setting, the idea could potentially be transferred to other organs.”

Cheng hopes to manufacture the therapy at the Columbia Initiative in Cell Engineering and Therapy and to conduct a phase-one safety trial at Columbia University Irving Medical Center, which is across the street from his lab.

"We can leverage our in-house resources for manufacturing and then start a clinical trial," Cheng said. "Columbia can do both."

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