The new technology that is revolutionizing medicine

Cima researchers Dr. Amaya López-Pascual, Dr. Antonio Fontanellas, and Dr. Pedro Berraondo explain the clinical applications of messenger RNA (mRNA), a new technology that is revolutionizing medicine.

Amaya, Antonio, and Pedro have several things in common: in addition to being researchers at Cima, all three apply messenger RNA in their different lines of study, all three work with Dr. Matías Ávila, and all three have published their studies in different scientific journals. In this three-way conversation, they reflect aloud on the virtues of this new technology.

Dr. Matías Ávila, Dr. Amaya López-Pascual, Dr. Antonio Fontanellas, and Dr. Pedro Berraondo.

Amaya López-Pascual (AL-P): Antonio, could you briefly explain what mRNA is?

Antonio Fontanellas (AF): mRNA is a molecule that transfers genetic information from the DNA in the nucleus to the place in the cell where proteins are produced. Technology based on the use of synthetic mRNA molecules is revolutionizing medicine, enabling the creation of innovative, personalized therapies to treat infectious, inflammatory, genetic, and oncological diseases.

Pedro Berraondo (PB): Exactly. We can use mRNA as a messenger that carries the instructions necessary for cells to produce specific proteins for therapeutic purposes. This is crucial for the development of vaccines and new gene therapies.

AL-P: Antonio, could you tell us how you use mRNA in your research on rare diseases?

AF:  In our laboratory, we are investigating the use of mRNA to correct protein deficiencies in rare genetic diseases, such as hepatic porphyrias. We use lipid nanoparticles to encapsulate the mRNA, protecting it and facilitating its efficient delivery to liver cells. These nanoparticles act as precision vehicles, transporting the mRNA directly to liver cells to ensure that the treatment acts where it is really needed. In addition, by modifying these lipid nanoparticles, we can target the mRNA to other cells, such as those in the bone marrow, muscle, or lung, thus broadening the spectrum of diseases that can be treated.

PB: It's fascinating how these nanoparticles can be designed to target specific cells. In my case, I'm working on cancer immunotherapy. In this field, one of the most promising applications of mRNA is personalized vaccines that stimulate the immune system to attack specific tumor cells.

AL-P: Pedro, can you elaborate on how these personalized vaccines work?

PB: Personalized cancer vaccines are created by selecting molecules specific to a patient's tumor. We then encode these molecules into mRNA and encapsulate them in nanoparticles. When administered to the patient, these nanoparticles stimulate the immune system to recognize and attack tumor cells. This technology offers new hope in cancer treatment.

AL-P: In my case, I am researching the use of mRNA in metabolic diseases such as metabolic steatohepatitis, obesity, diabetes... In collaboration with Moderna, we have shown that treatment with mRNA encapsulated in lipid nanoparticles can significantly improve the condition in preclinical models. This treatment has the potential to offer a more effective and less invasive solution for patients.

And in the recently published study, mRNA has been applied to the treatment of acute pancreatitis, a disease with no specific therapeutic options beyond symptom control. In this case, lipid nanoparticles transport mRNA to produce the two proteins necessary for the regulation of metabolism and inflammation in the liver.

PB: It is very exciting to see how mRNA can be applied in different areas of medicine. In addition to our individual research, Cima collaborates with companies such as Moderna and BioNtech, and participates in strategic projects such as ARNMUNE, funded by the Government of Navarra and coordinated by Cima. These efforts seek to apply mRNA technology in innovative and effective treatments.

It is important to note that these collaborations allow us to move forward more quickly and efficiently. For example, the ARNMUNE project aims to develop mRNA-based cancer immunotherapies. This study seeks to stabilize the RNA molecule, find an appropriate vehicle for its transport, and create specific RNA molecules to elicit an immune response against the tumor.

AL-P: What are the main challenges we face in our research?

AF: One of the biggest challenges in the therapeutic use of mRNA is its stability. Naturally, this molecule is very unstable and degrades quickly. However, we have made progress in techniques to stabilize it, modifying the molecule and encapsulating it in lipid nanoparticles. Another challenge is the specific delivery of mRNA to target cells without triggering an adverse immune response, a crucial aspect for its safety and therapeutic efficacy.

PB: In addition, the customized production of mRNA vaccines for each patient represents a logistical and economic challenge. Identifying the specific neoantigens of each tumor and producing the corresponding mRNA requires time and resources. We also need to conduct larger clinical trials to consolidate initial results and ensure the efficacy and safety of these therapies.

AL-P: What recent advances have we made in our research?

AF: We have recently developed a key animal model for investigating rare diseases such as acute intermittent porphyria. This model has allowed us to confirm the safety and efficacy of systemic treatment with mRNA in lipid nanoparticles. We have verified that repeated administration does not generate adverse immune responses, which is a major advance for its clinical application.

PB: In the field of cancer immunotherapy, we have made significant progress with mRNA vaccines. An mRNA vaccine is in the final phase of clinical trials in patients with metastatic melanoma. If the results are positive, its use in other patients will be approved. In addition, we are working on strategies to modify T cells with mRNA to express specific proteins that attack tumors, which has shown promising results in preclinical models.

AL-P:  In the field of metabolic diseases, we have managed to significantly improve the condition of preclinical models of metabolic steatohepatitis, reduce body fat, and improve insulin sensitivity with a weekly dose of FGF19 mRNA encapsulated in lipid nanoparticles for six weeks. This breakthrough could offer a new treatment option for patients with this disease.

And in the case of acute pancreatitis, the results of our study show that a single administration of FGF21 and APOA1 mRNA reduces pancreatic and liver damage in experimental models, suggesting a protective and anti-inflammatory effect. mRNA has the potential to transform the clinical landscape and improve patients' quality of life. The advances we have made and the future possibilities are very encouraging

¿Qué es el ARN mensajero?

El ARNm es una molécula que lleva la información genética del ADN a los sitios de l las células donde se producen las proteínas. Esta tecnología ha revolucionado la medicina, permitiendo la creación de terapias innovadoras y personalizadas.

Ventajas del ARNm

  • Rapidez y eficiencia: Las terapias basadas en ARNm son de producción rápida y pueden producir efectos terapéuticos en cuestión de minutos.
  • Seguridad: Tanto el ARNm como las nanopartículas lipídicas pueden modificarse para minimizar su interacción con sistema inmunitario, reduciendo el riesgo de reacciones adversas. A diferencia de las terapias génicas tradicionales, el ARNm actúa exclusivamente en el citoplasma sin ingresar al núcleo celular, lo que garantiza un efecto  transitorio sin cambios permanentes en el genoma.
  • Versatilidad: El ARNm puede ser modificado para tratar diversas enfermedades, desde condiciones metabólicas, hasta enfermedades infecciosas o cáncer.