• Date: February 28, 2020

300 million people worldwide suffer or will suffer at some time in their lives from a disease classified as 'rare'. One such disease is type 1 myotonic dystrophy, a neurodegenerative disease of genetic origin with often devastating consequences and that no treatment to date. On the occasion of World Rare Disease Day, we spoke with Rubén Artero, who leads the TATAMI project, which received a ”la Caixa” Health Research grant in 2018, and Beatriz Llamusí, a fellow researcher in the project, who received a CaixaImpulse grant in 2017 to enhance the therapeutic approach they have developed in their fight against the disease. Together with their team, the Translational Genomics Group at the Institute of Health Research INCLIVA, which is also affiliated with the Department of Genetics of the University of Valencia, they are designing the first effective treatment that, in addition, could be used to treat other rare diseases and even some cancers that share a common molecular mechanism.

TATAMI project team: From left to right: Beatriz Llamusí, María Sabater, Irene González, Nerea Moreno, Estefanía Cerro, Jorge Espinosa, Piotr Konieczny, Sarah Overby, Arturo López, Águeda Blázquez, Iván Gimeno and Rubén Artero. Credit: Arturo López

What are the challenges that a person suffering from this disease faces?

BEATRIZ: Type 1 myotonic dystrophy produces defects in the nervous system, skeletal muscles and the heart that, in the long run, cause cardiac and respiratory failure. But it also affects cognition and that is why the people who suffer from it are apathetic people, who always feel tired and sleepy. It can manifest itself at any age and, in fact, the sooner it does, the worse the diagnosis. It is a complex disease. Its symptoms vary greatly from person to person and this makes it much more difficult to find a treatment.

However, your project is close to developing a first effective drug.

RUBÉN: That's right. The origin of the disease is in a genetic mutation that causes proteins, called MBNL1 and MBNL2, to be sequestered. Without these proteins, the cells do not work well and the sympoms of the disease occur. We discovered that, in addition to the mutation, in the patients' cells there are also two regulatory molecules, of the microRNA type, that prevent more of these proteins from being produced to compensate for those that are sequestered. And it occurred to us that, if we were able to inhibit these microRNAs, we could make the cells produce MBNL1 and MBNL2 and, with that, reverse the symptoms of the disease.

And have you achieved it?

BEATRIZ: So far, we have managed to reverse them in cell cultures and murine models. For this we have designed and patented molecules that act as antagonists of these microRNAs. They join to them and then block them. They are what are called ‘antagomiRs’. Our therapeutic approach is totally innovative, since the action of these microRNAs in myotonic dystrophy type 1 was previously unknown and, therefore, we did not have this target to fight against.

What phase of the project are you in?

BEATRIZ: Three years ago we were selected in the CaixaImpulse programme, which allowed us to make a plan to valorise our idea, to see if it was feasible to take it to the market and turn it into a treatment for patients. That was just beginning. Then, with a research grant from the ”la Caixa” Health Research programme, we have managed to do the preclinical development. Soon we will begin to test the drug with human patients. Thanks to these grants, we have created a spin-off company called Arthex Biotech, linked to the University of Valencia, which will continue with the development of the treatment.

RUBÉN: We have designed about 100 different molecules and we are testing them in the laboratory, to select the best candidate for the drug. That is, we are in a process of selecting the most specific, effective and safe candidate to then carry out our first clinical trial with humans.

When studying rare diseases, the collaboration of patient associations must be essential.

RUBÉN: For us, their support is very important because they allow patients from different parts of the world to join forces and generate synergies. In addition to our team at the INCLIVA Health Research Institute; we have also collaborated with research groups from the Institute for Bioengineering of Catalonia (IBEC), the University of Oxford, the Imagine Institute of Paris in this project.

BEATRIZ: Our research also opens the door to treatments against other genetic diseases in which similar molecular mechanisms are involved, such as spinocerebellar ataxia type 8 and fragile X chromosome disease. In addition, MBNL proteins are related to different types of cancer; specifically, breast cancer and hepatocarcinoma. So, from this work, in the long run, it could offer treatment possibilities for many people. We are very excited about this therapeutic approach.

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