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03 July 2018

A Potential Treatment for Heart Failure Using mRNA to Boost VEGF-A Production in the Heart

Regina Fritsche-Danielson
Senior Director and Head of Bioscience Heart Failure, IMED Biotech Unit, AstraZeneca

It isn’t often that a group of scientists get to work on something as exciting as heart muscle regeneration. But a joint research team from AstraZeneca and Moderna have seen encouraging results by stimulating the growth of new blood vessels at the borders of damaged heart muscle tissue.

Until now, our heart regeneration research has been in the laboratory. But thanks to a highly productive collaboration between our two companies, we have moved into our first Phase 2 clinical study in patients with heart failure who are undergoing coronary artery bypass surgery.

New therapies for heart failure are urgently needed, as an estimated 26 million people around the world are living restricted lives due to this condition.

Heart failure occurs when the heart can’t pump blood efficiently around the body. It’s usually due to damaged heart muscle, which is often the result of a heart attack. It occurs mainly in older people, and the number of those impacted is rising as more people live longer. In Europe and the U.S., more than a million people are admitted to the hospital with heart failure each year. The disease can leave these patients breathless and fatigued, making it hard to perform daily activities that the rest of us take for granted.

Heart failure is frequently treated with drugs that control blood pressure and improve the pumping action of the heart, or from surgically implanting a pacemaker. Yet none of these interventions address the underlying cause of heart failure – diseased or damaged heart muscle caused by inadequate blood supply.

We’re hoping that our heart muscle regeneration research will change that. AstraZeneca has an extensive cardiac regeneration research program that is identifying new targets and pathways involved in repairing damaged heart muscle.

At the center of our research is a naturally occurring growth factor that stimulates formation of new blood vessels and protects heart muscle cells from dying. It’s called vascular endothelial growth factor A (VEGF-A).

For more than 20 years, other researchers have tried to turn VEGF-A into a treatment for heart disease. These efforts have included using systemic injections of recombinant VEGF-A protein to try to improve the blood supply to damaged heart muscle and gene therapy to deliver sequences of DNA with the genetic blueprint that cells need to make VEGF-A. Yet all these previous efforts have been met with limited success.

Since 2013, AstraZeneca has collaborated with Moderna on a different approach. This involves using messenger RNA (mRNA) – the process by which genetic information contained in DNA is transferred to make proteins. Through this collaboration, we are testing the effects of injections of VEGF-A mRNA into heart tissue to trigger production of the protein (click here for additional background).

In preclinical studies, we have seen new blood vessels appear at the borders of damaged heart muscle. This was in response to injections of VEGF-A mRNA carefully targeted at areas where oxygen levels were low. More than that, we have also seen improved cardiac function in these preclinical models as a result of the improved blood and oxygen supply being delivered to the heart.

By using mRNA, we aim to maintain precise control over how much VEGF-A is made. This reduces the risk of side effects such as leaky blood vessels and tissue oedema, which can appear if the VEGF-A signal is turned on for too long.

Perhaps the largest breakthrough in our research came when we discovered we could inject a simple solution of ‘naked’ mRNA directly into heart muscle. In the case of VEGF, this meant there was no need to wrap the mRNA in a protective coating to protect it from enzymes in the blood that could break down the mRNA before it reached the inside of cells where it acts.

This was an unexpected and exciting finding as it appears that uptake of ‘naked’ mRNA is only possible in skin and heart tissue. This finding enabled us to progress our research more quickly than expected.

Where do we go from here? Heart failure is our number one priority, but there are other obvious areas to take regeneration therapy, including chronic kidney disease, serious burns and other complex wounds where there is a need to improve the blood supply to damaged tissue.

Being part of the team that is making such exciting advances is hugely rewarding. Working with Moderna, we have already made significant progress overcoming issues – and believe this is just the beginning for heart failure and other regeneration therapies.

Regina Fritsche-Danielson