Entering a new era in vascular and cardiac regeneration …

When I started my working life in a pediatric intensive care unit, I could not possibly have imagined that, 30 years later, I would be living through a phenomenal scientific revolution in which we are using mRNA to give the instructions a cell uses to make proteins. Even as recently as 2003, when the human genome was cloned and we were all brimming with curiosity about what it meant for DNA-based therapies, I do not think we realized that mRNA therapeutics would prove so attractive.

The beauty of mRNA therapy is that it acts locally and transiently. We are not trying to integrate it into a persons genome, as we would with DNA, and make a permanent change. What we are doing is trying to accelerate and improve what the body does on its own.

With VEGF-A mRNA in heart failure, we are aiming to boost the bodys own healing mechanisms. We know, for example, that the body produces more VEGF-A after a heart attack to try and prevent heart muscle damage. We have also seen that there is a fine line between the amount of muscle damage that has very little effect on a patients life and the amount that leaves them waking up at night short of breath and unable to live normally.

Our preclinical and pathophysiological models suggest that, following a heart attack, a single intervention could have the potential to allow a patient to produce enough VEGF-A, for long enough after an injection, to enable them to self-heal and not be left with potentially life-changing heart failure.

Injecting someone with mRNA very precisely into their heart after a heart attack may sound scary. But cardiologists already routinely put drug-eluting stents into the coronary arteries and carry out bypass surgery. We expect such targeted treatment will not be a barrier to mRNA therapy for heart failure.

Modernas collaboration with AstraZeneca to discover and develop a potential mRNA therapy for heart failure has been very productive, as our teams have a shared sense of mission and urgency but complementary skills and competencies. At Moderna, we have had success in producing our mRNA with the right process and purity so that the immune cells did not see them as invader and attack them, while AstraZenecas expertise in drug delivery and cardiovascular medicine has enabled VEGF-A mRNA therapy to move into clinical trials.

To successfully get mRNA therapies into cells, we have worked through a lot of research steps. These have included optimising the chemistry of the mRNA and the way we make it and formulating it into a drug that gets through cell membranes. No single advance has provided all the answers, and we have needed a pharmaceutical engineering mind-set to work out how to solve all the problems. The good news is that, like digital software, our optimized mRNA platform is highly reproducible and we can use it again and again to make mRNAs for different proteins.

In collaboration with AstraZeneca, we are now moving ahead with the development of a relaxin mRNA for the treatment heart failure. Relaxin is a natural hormone that works during pregnancy to enable a womans cardiovascular system to adjust to her need for increased blood volume and cardiac output. We want to use mRNA to boost production of relaxin in people with heart failure to achieve a similar effect in increasing cardiac output to meet the bodys needs. A recombinant protein form of relaxin has already been tested in heart failure but failed to improve outcomes. We believe that this is because relaxin has a short half-life, and it is not practical to infuse it for a long enough period to achieve the required effects. We want to develop an mRNA which results in production of a form of relaxin that has an extended half-life so tissue exposure will be longer and, hopefully, will result in a clinical benefit.

In the longer term, we envision patients being given combinations of mRNA therapies to treat cardiovascular and other diseases. As scientists, we tend to take a reductionist approach to treatment whereby we address one target at a time. But the body does not work like that. It is continually using dozens of mRNAs to simultaneously make dozens of proteins. Based on our experience at Moderna of using multiple mRNAs for vaccines, we believe that it should be relatively straightforward to extend that approach and combine mRNAs for future drug therapies. The challenge will come in choosing the right combination, in the right ratio.

As we move forward with mRNA therapies, our main priority should be to marry the exciting scientific innovations we are making with the unmet clinical needs that are still, in the real world, leading to significant numbers of deaths and limiting peoples lives.

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Entering a new era in vascular and cardiac regeneration ...