Heart disease is the leading cause of death in the US, with one person dying every 34 seconds from cardiovascular conditions. The US sees 800,000 heart attacks, also known as myocardial infarctions, per year, causing untold damage to cardiac tissues. The body replaces damaged cells with fibrotic scar tissue that can incite further long-term cardiovascular disease and – eventually – heart failure.
But what if this decline could be prevented?
A study published in Science from Columbia University researchers may provide a solution. Using self-amplifying RNA (saRNA), biomedical engineering professor Ke Cheng and his colleagues were able to up-regulate a peptide called pro-ANP (pro-atrial natriuretic peptide) in animal models that preserves cardiac function after a heart attack. They hope that their approach will change the prognosis for patients struggling with heart disease.
Young at heart
Scar tissue makes it difficult to recover after a heart attack, Cheng told BioXconomy.
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“When a heart attack occurs, many heart muscle cells die, and the adult heart has very limited ability to regenerate,” he said. “Current treatments can reopen blocked arteries and help patients survive, but they cannot effectively restore damaged heart tissue.”
However, the research team at Columbia University noticed something interesting in neonate animal models of heart attacks – a vastly increased ability to heal heart muscle tissue, all coming down to a peptide called ANP.
ANP is a natural cardioprotective peptide released by the body in response to cardiac stress and is encoded by the gene Nppa. Higher levels of pro-ANP, which is converted into its active form in the heart, correlate to greater cardiomyocyte regeneration.
The researchers observed a 25-fold upregulation of Nppa in neonate mouse models after myocardial infarction compared to just ten-fold in adults. Cheng and his team speculated that if they could introduce similar levels of Nppa in adults to those observed in neonates, this could provide regenerative effects.
The team focused their efforts on developing an RNA-based approach given the success of mRNA in vaccines, immunotherapy, and other areas. However, as heart attack patients are at an increased risk of developing heart failure in the first few months, the effects needed to last longer than traditional mRNA therapies.
“We were motivated by a question,” Cheng said. “How can we deliver long-lasting therapeutic signals to protect the heart without invasive procedures or repeated drug injections?”
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That led the team to saRNA – an emerging modality in RNA therapeutics.
A taste of your own medicine
saRNA has gained significant attention for its potency in mRNA vaccines against viruses and even brain parasites. Last year, Novo Nordisk invested in a $550 million partnership with Replicate to fund saRNA therapies.
A simple intramuscular injection turns skeletal muscle into a temporary ‘RNA factory.’
Cheng and his team at Columbia theorized that they could use saRNA-encoding Nppa to deliver long-acting expression of ANP without an invasive procedure.
“Traditional mRNA therapies can produce beneficial proteins in the body, but their effects are usually short-lived,” said Cheng. “saRNA can copy itself inside cells and produce much higher levels of therapeutic proteins for a longer period.”
Using saRNA avoids the need for a viral vector, limiting the risk of an immune response, while achieving similarly robust outcomes. As Cheng put it: “A simple intramuscular injection turns skeletal muscle into a temporary ‘RNA factory.’”
However, creating an intramuscular saRNA injection isn’t easy.
“RNA molecules are extremely fragile and can be easily degraded by enzymes called RNases, which are widely present in the environment,” he explained. “This challenge becomes even greater for saRNA because it is much longer than conventional mRNA, making it more vulnerable during synthesis.”
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“That required working under very strict RNase-free conditions and carefully optimizing the in vitro transcription process.”
Ironically, systemically high doses of active ANP come with several associated toxicities – meaning if their approach was successful, the drug could do more harm than good. That’s why the team turned to pro-ANP, the precursor of atrial natriuretic peptide, in order to create a cardiac-activated peptide which is converted in the patient’s own heart. This avoids the risks of systemically high doses of active ANP while also not requiring direct delivery to the heart.
“The drug is produced remotely but activated specifically in the target organ,” added Cheng. “This creates a type of ‘smart drug activation system,’ allowing a therapy generated in muscle to exert its effects primarily in the heart.”
From scarring to salvation
To test the effectiveness of their saRNA therapeutic, Cheng and his co-authors combined saNppa with lipid nanoparticles for delivery via intramuscular injection. They then tested their formulation in several animal models of myocardial infarction and other cardiac injuries compared to a control treated with saline solution.
With a single injection of saNppa, mice suffering from a heart attack had increased cardiac function across all doses when compared to the control group. Treated mice had a two-fold increase in serum pro-ANP levels, and after four weeks, had double the function of their left ventricles versus untreated mice.
The function of the left ventricle, the largest chamber of the heart, is an important predictive marker for heart failure. The left ventricles of treated mice had greater functional recovery with less heart strain, reduced fibrosis, and a smaller infarct compared to the control group.
The team was even able to replicate the protective benefits for heart function and recovery when saRNA treatment was delayed. Mice given a single injection of saNppa a week after their heart attack showed recovery of the left ventricle from 25% to up to 40% function after treatment. Thinning, dilation, and fibrosis of the wall of the left ventricle, a known pathology of heart failure, was also significantly reduced.
Self-amplifying RNA could enable long-lasting, minimally invasive treatments that combine systemic delivery with organ-specific activation.
Cheng and his colleagues also saw the same restorative results in myocardial infarction animal models representing aged heart tissue, atherosclerotic patients, and metabolic syndrome to mimic type II diabetes. All showed improved left ventricle function and reduction in tissue scarring. Even pig models mimicking ischemia and reperfusion heart injuries showed a three-fold benefit in cardio protection versus control.
Cheng and his coauthors noted that they achieved these results with no observed systemic toxicity and only local inflammatory responses at the site of injection. This is particularly noteworthy given viral therapies have recently come under scrutiny for causing liver toxicity, linked to contaminants in manufacturing.
“Together, these findings show that self-amplifying RNA could enable long-lasting, minimally invasive treatments that combine systemic delivery with organ-specific activation,” Cheng said.
Results certainly seem promising, but Cheng was quick to note that there is still significant work to be done in the space of saRNA therapies.
“We would like to better understand how different tissues respond to saRNA therapies and how we can further improve delivery efficiency and safety,” he said. “Looking ahead, our goal is to expand the range of biological therapies that can be delivered using self-amplifying RNA.”
Human clinical trials and overall safety and efficacy in cardiovascular patients will need to be established down the line. For now, these preclinical results certainly suggest this drug modality is one to watch.
“Ultimately, we hope this technology will lead to simple, minimally invasive treatments that allow the body to produce its own medicines,” Cheng concluded, “opening new possibilities for treating heart disease and many other conditions.”
Quotes have been lightly edited for clarity.