A new mRNA treatment to repair the heart after a heart attack

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During a heart attack, millions of heart cells (cardiomyocytes) die from lack of oxygen. Unfortunately, these losses are irreversible as these cells have no opportunity to regenerate. Depending on the severity of this deterioration, the risk of later heart failure and other heart diseases can be very high. However, researchers have found an innovative way to repair and regenerate damaged cells.

When the heart has lost too many cardiomyocytes, it ends up being exhausted and no longer (or poorly) performing its pumping function: this is heart failure. However, there is currently no drug that can restore heart function; Transplantation remains the only option, but the low availability of donor hearts and the risk of rejection limit its widespread use. Therefore, scientists have been trying for decades to find a way to regenerate heart cells.

Several teams are betting on the use of stem cells, which could be differentiated into cardiomyocytes. However, this approach has certain problems: the use of embryonic stem cells and induced pluripotent stem cells in particular carries a risk of teratoma (a type of tumor) formation. A University of Houston team focused on the serum response factor (SRF), which plays an important role in regulating the cell cycle by directing the transcription of many genes.

A condition close to that of stem cells

The heart is the first functional organ to develop during embryogenesis, and SFR is necessary for the formation of sarcomeres — the basic units of myofibrils in the heart muscle — and the first heartbeat.

Researchers generated a series of mutant SRF proteins that allow adult myocytes to rejoin the cell cycle. ” We are trying to dedifferentiate the cardiomyocytes into a more stem cell-like state so they can regenerate and proliferate. says Siyu Xiao of the University of Houston’s Department of Biology. To deliver these transcription factors to heart cells, the team used synthetic mRNA — the same technology used for COVID-19 vaccines, which involves tricking cell ribosomes into producing specific proteins.

One of these mutated proteins, believed to be the strongest, has been named STEMIN. Tested in rat myocyte cultures, STEMIN’s synthetic messenger RNA promoted partial reprogramming into a strain-like state and caused cardiomyocyte dedifferentiation. Another mutated SRF protein called YAP5SA directs a variety of growth factors to proliferate dedifferentiated myocytes.

The team injected STEMIN and YAP5SA mRNA individually and then in combination directly into the left ventricle of live adult mice that had suffered myocardial infarction. The aim is to test whether this “treatment” could be used to reprogram the myocytes so that they enter the cell cycle and thus repair the damaged heart. ” The results were stunning said Robert Schwartz, who co-led the study with Xiao.

Hearts repaired in a day

The combination of the two mRNAs has been shown to be particularly effective at restoring heart function – far more effective than either mRNA taken individually. After injection of these transcription factors into the heart of mice, myocyte nuclei replicated at least 15 times (and up to more than 17 times) in 24 hours! ” The lab found that heart muscle cells multiplied rapidly within a day, while hearts were repaired over the next month to return to near-normal pumping function with little scarring. ‘ says Schwartz.

The illustration shows a repair example live Heart of an adult mouse who had suffered an infarction via injection of a combination of mRNA STEMIN and YAP5SA. After four weeks, the cut and stained hearts show a significant reduction in the injured area. © The Journal of Cardiovascular Aging

STEMIN and YAP5SA promoted cardiomyocyte proliferation by inhibiting SRF-dependent cardiomyocyte differentiation, thereby shifting cardiomyocytes to a more primitive stage to promote cell replication summarize the researchers in The Journal of Cardiovascular Aging. This unprecedented approach has made it possible not only to repair heart muscle cells in mice, but also to regenerate them after a heart attack. ” No one has been able to do this to this extent and we believe it could become a possible treatment for humans. », emphasizes Schwartz.

An additional advantage of using synthetic mRNA as a delivery vehicle, according to Xiao, is that it disappears on its own within a few days, unlike viral transmission. Indeed, gene therapies delivered to cells by viral vectors raise several biosafety questions as they cannot be easily stopped. ” Adenovirus delivery of stem cell factors is initially curative to regenerate cardiac function, but in the long term causes cardiac rhadomyosarcoma ‘ says the team.

Note that this mRNA-based method of gene delivery also allows the delivery of combinations of genes with different ratios, allowing treatment to be personalized for each patient according to the evolution of the disease.

Source: S. Xiao et al., The Journal of Cardiovascular Aging

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