“RNA is the medicine of the future and the first step in personalized medicine”

Because perhaps the happiness this project is bringing to the entire team is the closest thing to a dream for any scientist. Work started in 2005. That year Malu took charge of the ‘Liver Disease Lab’, one of the laboratories that make up the scientific ecosystem of CICbiogun of Vizcaya. His research focused on finding a cure for liver diseases and it was his keen eye that discovered that, between the microscope and the petri dish, the key might lie in magnesium, a compound that appeared altered in all patients. “We wanted to identify whether the magnesium changes we saw in patients with liver disease were due to adipose tissue or whether the liver had something to say,” he explains. To do this, they began a “very, very detailed” study that led them to the molecule that held the key to the entire process.

This is the CNNM4 transporter, a molecule that transports magnesium in the human body and which appears to be “particularly induced” in patients with liver damage. He explains that the pattern was the same whether they were suffering from fatty liver, damage caused by alcohol, cholangiocarcinoma or damage caused by paracetamol overdose. “Having discovered this pattern, we wanted to see what happened when healthy hepatocytes (liver cells) were exposed to excessive levels of this transporter,” he says, and his lab’s mice revealed that It was CNNM4 that caused liver damage. That is, the transporter did not appear as a result of the damaged liver, but rather it was the “conductor” that made the organ sick.

Martínez-Chanter and his team were clear that the solution was to find a very specific system that could “silence”, or at least “modulate” the activity of that molecule in the liver, affecting the function of others in the body. Without doing. parts. It is to this point of research that he relates to the great hermeneutic potential, where messenger RNA technology has provided the icing on the cake of research. Because, although it is a ‘fashionable’ treatment in modern medicine, it has been introduced in the ‘Liver Disease Lab’ after the success of the vaccines against Covid-19 or the awarding of the Nobel Prize in Medicine to the creators of this technology. Who were experimenting on this for a long time. “We thought the best approach was to use a therapeutic RNA that was able to reduce the levels of that molecule in the liver cell,” he explains.

four thousand tests

When she tells it, it sounds like a simple process, but finding the ideal molecule cost a team of a dozen researchers more than 4,000 tests. Thus, they managed to combine an RNA capable of reducing the CNNM4 transporter in the liver with GalNAc, a sugar widely used in biochemistry for its conjugation ability. Those were years of trial and error, recalls Martínez-Chanter, who would not have succeeded in these years without the teamwork and collaboration of Naroa Goikoetxea, Malu’s right-hand man and who would also have been in the company that developed the project. “It was complicated because we wanted it to act on the CNNM4 transporter without touching the expression of any other genes,” he summarized.

But they eventually managed to find a “very stable” molecule that remains in the body for “four weeks” and can be administered by subcutaneous injection, “as if it were heparin.” Once injected, it goes to the liver, where there is a receptor that is able to recognize it and thus “manages to control the expression of the gene that is causing this damage” ” As a result, in the trials conducted so far it has managed to reverse the damage caused by disorders that so far lacked effective treatment with “very minor” side effects.

towards personalized medicine

However, the importance of its creation goes beyond helping liver patients. Martínez-Chanter is clear that therapeutic RNA is part of the “medicine of the future.” Be that as it may, we are encouraged to “dream” of being the first step in personalized medicine that manages to act on the genes that cause incurable pathologies with less impact than conventional drugs. “Because it’s so specific, we’re directing it specifically to the organ and cell we want,” he explains.

A dream that seems huge and who would now like to do his work from his own small laboratory. With the subsidy from ‘La Caixa’ he hopes to found a company that will allow him to “close the circle” that any scientist aspires to and will be able to develop treatments. “For me and my team, the training is essential, along with the program, so we can open our eyes and see where the resources are,” he admits. And for your happiness to be complete, you still have a long way to go.

The molecule that has been proven effective must now pass testing by certified laboratories that will verify both its effects and the absence of toxic damage. And then it will have to go through clinical trials, “about five or six years in total.” In the meantime, they are already working to see if their technique could also be effective in diseases like pulmonary fibrosis or kidney fibrosis, where abnormal levels of the magnesium transporter have also been detected. “So far we have been able to generate a molecule to treat it and in the future we will have to see if it also works in the clinic with patients,” he concluded.