A team of researchers led by scientists at Columbia University has developed a potential treatment designed to help the heart recover after a heart attack by prompting the body to produce a protective hormone. The therapy, described in research published in Science, is delivered by a single skeletal muscle injection containing self-amplifying RNA packaged in lipid nanoparticles, which encodes the gene for atrial natriuretic peptide (ANP), a hormone that can reduce stress on the heart and support repair after injury.
“This is about helping the heart tap into its own healing mechanisms,” said study co-author Ke Huang, MD, PhD, a former research associated at Columbia, and now assistant professor in the Texas A&M Irma Lerma Rangel College of Pharmacy. “We’re trying to give patients a treatment that works with the body rather than against it. And the idea that a single shot might offer support for weeks is very exciting.”
Heart attacks damage heart muscle and can initiate a process that eventually leads to heart failure. “Myocardial infarction (MI) causes irreversible loss of cardiomyocytes and adverse remodeling, ultimately progressing to heart failure,” the researchers wrote.
Current treatments after a heart attack try to repair or protect injured heart tissue, but therapeutic delivery or durability of treatments have limited their effects.
The new treatment was engineered to overcome those limitations. The therapy uses self-amplifying RNA, or saRNA, delivered through lipid nanoparticles in a formulation called saNppa-LNP. The RNA encodes natriuretic peptide type A (Nppa), the gene responsible for producing ANP, a hormone normally released by the heart in response to stress. ANP helps regulate blood pressure and fluid balance and can limit strain on cardiac tissue after injury. However, the body typically produces only small amounts following a heart attack. In the study, the scientists sought to amplify that natural response by instructing skeletal muscle cells to produce additional ANP precursor protein that circulates in the bloodstream.
Once injected into skeletal muscle, the RNA instructs cells to produce the precursor of ANP, allowing the body to circulate the protective signal during the period when the heart is vulnerable to damage and remodeling following myocardial infarction.
“We hypothesized that a single intramuscular (IM) injection of an saRNA-LNP encoding native Nppa (saNppa-LNP) could establish an in vivo ‘RNA factory,’ continuously producing circulating pro-ANP that is selectively activated into functional ANP in the heart by the cardiac protease corin, thereby providing durable cardioprotection without direct cardiac manipulation,” the researchers wrote.
The research team tested the therapy in multiple experimental models of heart injury. In mouse models of acute myocardial infarction and ischemia-reperfusion injury, a single injection improved left ventricular ejection fraction, reduced infarct size and decreased fibrosis compared with control groups. The researchers also tested the therapy in models representing conditions frequently seen in patients with cardiovascular disease, including aged, atherosclerotic and diabetic mice.
The team also conducted large-animal experiments of the treatment. In a swine model of ischemia-reperfusion injury, a single intramuscular dose preserved cardiac function and reduced maladaptive remodeling.
The concept builds on earlier work by members of the research team including the development of a microneedle patch that delivers a hormone directly to the surface of the heart to promote repair after myocardial infarction. That researcher identified a signaling pathway linked to the natriuretic peptide receptor NPR1 as a potential mechanism that could support heart healing. Because ANP is the natural ligand for the receptor, the new research sought to determining if increasing ANP levels could elicit the same response as the microneedle patch using a less invasive approach.
“Our study demonstrates that a single IM administration of saNppa-LNPs provides robust and durable cardioprotection across multiple species and clinically relevant injury models,” the researchers wrote. “By leveraging the self-amplifying properties of saRNA and the heart-specific activation of pro-ANP, this minimally invasive, one-shot therapy may offer a safe, simple, and effective strategy for cardiac repair.”
Follow-up preclinical research will focus on evaluating the safety, determining dosing strategies, and treatment timing in advance of in-human studies. If subsequent studies confirm the findings, the therapy could eventually be administered soon after a heart attack to support the heart during the early phase of recovery, when stress on the injured tissue is highest and the risk of long-term remodeling is significant.
