Mauro Giacca: "There is a tremendous need to achieve cardiac regeneration"

Dr. Giacca is Head of the School of Cardiovascular and Metabolic Medicine and Sciences, Professor of Cardiovascular Sciences at the Faculty of Medicine and Life Sciences, King’s College London, and President of the International Society for Heart Research (ISHR) European Section. He is also a founder of Forcefield Therapeutics and Heqet Therapeutics, two recent start-ups that are developing biological cardiovascular devices, and co-founder of Purespring Therapeutics.

A physician by training, Dr. Giacca is considered an expert in the generation of viral vectors for cardiovascular applications and in the development of novel biologics for cardiac repair and regeneration after myocardial infarction and heart failure. His group has achieved the regeneration of cardiac tissue after damage caused by a myocardial infarction. He also has a great interest in the molecular biology of HIV-1 infection.

Your group managed to regenerate cardiac tissue after damage caused by a myocardial infarction. What was the key?

What we did was conduct a high throughput screening with molecules that seem to work, although we have not been able to understand what really happens. We started by trying out multiple treatments on cardiomyocytes to see which worked. We have different treatments that were able to promote cardiac proliferation, the most promising of which were microRNA. And it worked in mice and pigs! The problem is that our ideas cannot be applied to patients due to the form of delivery. Now, we are using viral particles that contain RNA as vectors, which is the same technology that Moderna and Pfizer used in their COVID vaccines. And we are still looking for the perfect particle for the heart.

The way we see our approach is: a patient with a heart attack is treated with catheterisation in a hospital to unblock an arterial occlusion (the cause of the infarction) allowing the blood to flow. The idea is, at the same time or a few days later, to inject these lipid particles with RNA into the coronary artery to promote the proliferation of existing cardiomyocytes, thus achieving regeneration.

We know that regeneration will not be complete, because that depends on the size of the lesion, but although it only works 30%, 40% or 50% there will always be a clinical benefit.

So, we should talk about partial heart regeneration?

That’s not our idea, because what we want is complete regeneration. But this isn’t like cancer, where you have to kill all of the tumour cells because if you leave one, the cancer will reproduce. In the heart, although therapy is not completely effective, there is a clinical benefit.

In the future, will it be possible to regenerate the heart after a heart attack?

Of course; we are not far away from achieving it. There is a tremendous need to achieve cardiac regeneration. The way I see it, it is very simple. We know that cardiac cells, cardiomyocytes, lose their capacity to proliferate after birth. Data shows that a 70-year-old person has at least 50% of their cardiac cells with the capacity to regenerate themselves that they had when they were born. Which is to say that the capacity to regenerate the heart throughout life is minimal, and clinically irrelevant. This means that when a person suffers a heart problem, like a heart attack, when part of their heart suffers necrosis or dies, there is no way to recover the lost cardiac cells. And this occurs due to the inability of cells to regenerate. This situation is not dissimilar to what occurs in other organs, like the brain. We are born with a certain amount of neurons, but the capacity of these cells to proliferate is inexistent. And we lose neurons throughout our life, so it is hardly surprising to see a rise in diseases associated with dementia as life expectancy increases. The same thing happens with sight or hearing; the cells of these organs don’t proliferate either.

We find ourselves without a treatment for these problems of dementia or cardiovascular disease, but we don’t have a cure for diabetes, loss of vision or hearing either, because we do not know how to regenerate cells.

I tell physicians they should tell their patients that when we are born, we are given these cells as a gift, and the better we look after this gift, the better our lives will be.

But in my opinion, cardiac regeneration is less complicated than regeneration of the brain. For the brain, not only is it necessary to generate new neurons, but they themselves must manufacture new connections in the brain. And that is very complicated because neurons are highly specialised to perform specific functions, like controlling movement. It is highly complex.

Nevertheless, things are easier in the case of the heart. And different. Cardiac cells are a lot simpler than neurons. They are mechanical cells that integrate in a relatively simple way with residual cells of the cardiac muscle to regenerate the heart. The problem we find is that the heart does not have stem cells that can be activated.

There are two ways of attempting this regeneration of the heart. The first is to produce the cells in the laboratory and later implant them in the patient and the second is to convince the cardiac cells of the heart to proliferate

What are the current approaches?

There are two ways of attempting this regeneration. The first is to produce cells in the laboratory and later implant them into the patient, whereas the second is to convince the cardiac cells of the heart to proliferate. Both options are front-line.

We know how to produce cardiac cells from stem cells. After a myocardial infarction we lose at least 1,000 million cardiac cells. There are three clinical trials that are generating close to this figure of 1,000 million cardiac cells in the laboratory for implantation at the site of the heart lesion. The problem with these approaches is that the cells generated are at a very embryonic stage and have difficulties communicating with the patient’s cells. They do not have the same connections.

Currently there are attempts to mature the cells so that they can communicate better. But laboratory tests show that within the first three weeks this treatment produces fatal arrhythmias.

The other possibility, based on stem cells is, instead of implanting them directly in the patient, to create a type of cardiac tissue in the laboratory that has contractility and can later be surgically implanted in the heart. This is being done in two laboratories in Germany and is being tested in 8 patients in Göttingen. But this is a very complicated, expensive procedure, as well being very difficult to transfer to a routine clinical setting.

The most attractive idea is to convince residual cardiac cells to regenerate themselves. We know that some animals, like the salamander or zebra fish, or even newborn mice or pigs, are able to regenerate their hearts. This means that it is possible.

There is an anecdotal case of a child in Vienna who had a heart attack shortly after birth, something that is extremely uncommon. The child was treated with the latest technology to deal with the thrombus, but the damage to the heart was already done. Nevertheless, he underwent follow-up for years with MRI imaging tests and, amazingly, the tests showed that his heart was completely healthy. It had completely regenerated, something that had never been seen before. (The study was published in Circulation Research).

So, there is a reason why this does not happen in adults. In mice, we know that the window for regeneration to occur is two or three days. In humans, we think the window is longer, probably months.

Do we know what happens to cause this cell reprogramming?

This is one of the most fascinating mysteries, although we do have some hypotheses. For instance, we know that birth is one of the most traumatic moments for a living organism. Before, inside the mother, everything is easy. The heart of a newborn, outside the mother, has to begin to pump blood and make it circulate to all of the organs without the help of the mother’s heart. Also, unlike before birth, when the heart is very far from the lungs and receives blood with a small amount of oxygen, on birth, the heart connects to the lungs, so the blood contains a lot more oxygen.

Evidence exists of hormonal changes. There is probably a combination of events that tells the heart to stop dividing and make itself bigger because it has to start to work. The idea is to understand these signals in order to revert them.

As well as regeneration after a heart attack, your group is also working on preventing the damage produced by a heart attack. How?

Another of our approaches is to prevent damage, rather than regenerate cardiomyocytes. We have discovered three proteins capable of detaining the death of cardiac cells after a myocardial infarction. We believe that their use within the first 24 to 48 hours, or even in the ambulance, in a patient who has suffered a heart attack, could prevent the death of cardiomyocytes. The protein is injected into the vein to block the death of cardiomyocytes.So, in an ideal situation, we would have different alternatives: first, the use of proteins to prevent the death of cardiac cells and, subsequently, attempting to regenerate the heart with microRNA. Prevent death and regenerate. It is very ambitious.

You are a physician by training. Do you think that a good biomedical researcher should have a vocation to serve the patient?

Honestly, I have to say that when I decided to study medicine, I did it with the intention of going into research, although at that time I didn’t really know what a career in science was, and the image I had was a bit romantic. In fact, I haven’t done much clinical work with patients, but I think it is very beneficial for researchers to share a common language with clinicians. Having a solid basis of clinical practice makes it much easier to translate basic research to the patient. Of course, we want to know many things, mechanisms, regulatory genes, proteins, but we also want to develop therapies that benefit patients.