A novel RNA-based therapy developed by researchers at Columbia University aims to tackle the heart’s limited ability to regenerate after a heart attack, representing a significant advancement in cardiology.
A team of scientists at Columbia University has made strides towards addressing a longstanding challenge in cardiology: the heart’s inability to regenerate after injury. Their research, published in the scientific journal Science, introduces a new RNA-based therapy that could potentially enable the heart to heal itself following a heart attack.
Heart attacks often result in permanent damage to heart muscle cells, which do not regenerate once lost. Ke Cheng, the Alan L. Kaganov Professor of Biomedical Engineering at Columbia Engineering, explained, “The heart is one of the organs with the least ability to regenerate. The spontaneous regeneration power is very, very limited.” This limitation contributes significantly to the prevalence of heart failure among survivors of heart attacks.
Innovative Therapy Approach
Rather than simply preventing further damage, Cheng and his colleagues are pursuing a strategy that actively aids the heart in the repair process. Their experimental therapy is designed to transform the body into a self-producing drug factory. Instead of directly delivering medication to the heart, the therapy employs RNA to prompt other tissues to generate a healing molecule that becomes active only when it reaches the heart.
Cheng described the delivery method, stating, “You don’t have to open the chest or send a wire to the heart to deliver this drug. In principle, all the clinician needs to do is inject the particles into the arm.” This approach could fill a critical gap in cardiac care, as highlighted by study co-author Torsten Vahl, who noted the unmet need for effective treatments for patients left with severe heart damage post-heart attack.
Preclinical Study Results
In preclinical trials involving both small and large animals, a single injection of the RNA therapy notably reduced scar tissue and improved heart function. These promising results indicate a potential pathway toward simpler and more accessible therapies compared to traditional methods like transplants or cell-based treatments.
Research into the regenerative capabilities of newborn hearts has informed this innovative approach. Many mammals, including humans, exhibit a temporary ability to regrow heart muscle cells shortly after birth, largely due to a hormone called atrial natriuretic peptide (ANP). ANP promotes blood vessel growth, reduces inflammation, and limits scar tissue formation. However, as the body ages, levels of this hormone decrease significantly, limiting the heart’s regenerative capacity.
Investigating this phenomenon, Cheng’s team discovered that in newborn mice, the gene responsible for producing ANP’s precursor increased more than 25-fold following a heart attack. In contrast, adult mice only showed a 10-fold increase, which may insufficiently support cardiac repair. When the gene, known as Nppa, was blocked in newborns, their natural healing abilities were significantly impaired. “The whole idea is that we learn from nature,” Cheng remarked, emphasizing the need to bolster the mechanisms that facilitate heart regeneration.
Overcoming Delivery Challenges
Targeting the heart with drugs presents unique challenges due to its anatomical and physiological characteristics. Unlike other organs such as the liver and lungs, which can naturally absorb certain medications, the heart’s structure complicates targeted delivery. Traditional methods like direct infusions or injections into the heart muscle are invasive and typically require catheterization.
The researchers’ innovative approach involves a two-step method: first creating an inactive precursor within skeletal muscle, which is subsequently activated in the heart. The team engineered RNA-lipid nanoparticles that carry the instructions for producing Nppa. Once injected into the muscle, the precursor travels through the bloodstream, reaching the heart where it is activated by an enzyme called Corin, which is abundantly present in the heart.
Cheng explained, “Targeting is based on a specific cleavage of an enzyme that is naturally expressed in the heart. The idea is that you don’t have to touch the heart or open the chest. All you need to do is inject the arm.” To enhance the therapy’s duration, the researchers utilized self-amplifying RNA (saRNA), allowing the treatment to remain effective for at least four weeks after a single injection.
Future Directions
Before advancing to human trials, Cheng’s team is focused on testing the therapy under various realistic conditions. Their research included trials in large animals, older mice, and those with conditions that predispose them to heart disease, such as atherosclerosis and diet-induced type 2 diabetes. They also evaluated the treatment’s effectiveness when administered a week after a heart attack, revealing that it remained effective despite significant damage.
The collaborative study involved experts from Columbia’s Department of Biomedical Engineering, the Milstein Division of Cardiology, and the Institute of Comparative Medicine. Cheng noted, “We tested the drug in different disease comorbidities. 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 its applications in cardiac care, Cheng’s innovative RNA therapy could have implications for treating other conditions such as kidney disease, hypertension, and preeclampsia. Vahl emphasized the broader significance, stating, “Cell damage is a problem that not only affects the heart but many organs. 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 plans to produce the therapy at the Columbia Initiative in Cell Engineering and Therapy and initiate a phase-one safety trial at Columbia University Irving Medical Center. He expressed optimism about leveraging in-house resources for manufacturing and moving forward with clinical trials, stating, “Columbia can do both.”
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