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

Maria Luz Martínez-Chantar, known to everyone at the CIC bioGUne research center in Derio (Vizcaya) as Malu, is very happy. His project, a new technique that promises to fight incurable liver diseases thanks to RNA, has just received a grant of 150,000 euros from the La Caixa Foundation. The innovative treatment has already demonstrated its effectiveness in laboratory trials, and now the company dreams of using this money to complete the regulatory phase and test what the treatment of the future could be for many patients.

Because, most likely, the joy that a project brings to the entire team is the closest thing to a dream for any scientist. Work began in 2005. In the same year, Malu headed the “Laboratory of Liver Diseases”, one of the laboratories that make up the CICBiogune scientific ecosystem in Vizcaya. His research was focused on finding a cure for liver disease, and it was his visual acuity that revealed that between microscopes and petri dishes, the clue might be magnesium, a compound that appeared altered in all the patients. “We wanted to determine whether the changes in magnesium that we observed in patients with liver disease were caused by fatty tissue or whether the liver had something to say,” he explains. To do this, they began a “very, very exhaustive” study that led them to a 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. The picture was the same regardless of whether they suffered from fatty liver disease, alcohol impairment, cholagiocarcinoma or paracetamol overdose, he said. “Having discovered this pattern, we wanted to see what happens when healthy hepatocytes (liver cells) are overexposed to this transporter,” he says, and his laboratory mice showed that it was CNNM4 that caused liver damage. That is, the transporter did not appear as a consequence of liver damage, but rather became a “conductor” that made the organ sick.

Martinez-Chantar and his team clearly understood that the solution was to find a very specific system that could “silence” or at least “modulate” the activity of this molecule in the liver without affecting the function it could would be performed in other organs. parts. It is at this stage of the research that he talks with great didactic ability when messenger RNA technology became the icing on the research cake. Because, although this is a “fashionable” treatment in modern medicine, after the success of the Covid-19 vaccine or the award of the Nobel Prize in Medicine to the creators of this technology in the “Laboratory of Liver Diseases”, there has been someone experimenting with it for a long time. “We thought the best approach would be to use therapeutic RNA that could reduce the levels of this molecule in liver cells,” he explains.

Four thousand tests

When she tells it, the process seems simple, but finding the perfect molecule cost a team of a dozen researchers more than 4,000 tests. In this way, they were able to combine an RNA capable of restoring the CNNM4 transporter in the liver with GalNAc, a sugar widely used in biochemistry due to its ability to combine. It was years of trial and error, Martinez-Chantar recalls, that would not have been successful without the teamwork and cooperation of Naroa Goicoechea, Malu’s right-hand man during these years, who would also be part of the company developing the project. “It was difficult because we wanted it to act on the CNNM4 transporter without affecting the expression of another gene,” he summarizes.

But they have finally found a “very stable” molecule that lasts in the body for up to “four weeks” and is administered subcutaneously “as if it were heparin.” Once injected, it goes to the liver, where there is a receptor that can recognize it and thus “manages to modulate the expression of the gene that causes this damage.” As a result, the trials carried out so far are able to reverse the damage from pathologies for which there is still no effective treatment with “very few” side effects.

Towards personalized medicine

Although the importance of its creation goes beyond helping liver patients. Martinez-Chantar is clear that RNA therapeutics are part of the “therapeutics of the future.” Even, why not, we are encouraged to “dream” that this will be the first step in personalized medicine, which will be able to influence genes that cause incurable pathologies, with less effects than conventional drugs. “Because it’s so specific, we target it to exactly the organ and cell that we want,” he explains.

A dream that seems gigantic and that in its small laboratory would now like to contribute. With the help of La Caixa’s grant, he hopes to found a company that will allow him to “close the circle” that every scientist strives to achieve and develop a treatment. “For me and my team, the training that comes with the program is important because it allows us to open our eyes and see where the resources are,” he admits. And for your joy to be complete, you still have a long way to go.

The molecule, which has been proven effective, will now have to undergo testing in certified laboratories, which will check both its effect and the absence of toxicological harm. And then he’ll have to go through clinical trials, “only about five or six years.” Meanwhile, they are already working to find out whether their method could be effective in diseases such as pulmonary fibrosis or kidney fibrosis, in which abnormal levels of the magnesium transporter have also been found. “So far we have been able to create a molecule to treat it, and in the future we will have to see whether it will also work in the clinic with patients,” he concludes.

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