Researchers here describe a novel approach to encourage greater regeneration in heart tissue following the injury and lost function incurred during a heart attack. Their work falls into the growing category of practical gene therapies in which a small amount of easily accessible tissue, such as fat or muscle, is transfected to form a factory that generates and releases a beneficial circulating protein. Only a low dose of gene therapy vector is needed, and all of the present challenges in broader delivery of gene therapy are bypassed. The scope of possible uses is restricted to situations in which benefits can be derived from increased amounts of a specific protein in circulation, but this is still a large enough set of possibilities to support a broad industry.
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. 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.
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. For researchers the 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. In lab experiments, a single injection significantly reduced scarring and improved heart function in small and large animals.
Link: https://www.engineering.columbia.edu/about/news/new-rna-therapy-could-help-heart-repair-itself
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