Interview with Natividad Alcorta Sevillano, PhD, Biobizkaia Health Research Institute, Spain

(The header photo shows Dr. Sevillano with Dr. Lafaver and Dr. Crawford at OIF’s Investigator Meeting in Chicago)

Tell us about yourself and your work with OI!

My name is Natividad Alcorta Sevillano, and I am from a small town in the Basque Country called Urduliz. My doctoral thesis was in the field of OI, carried out in the group of Stem Cells and Advanced Therapies, at Biobizkaia Health Research Institute.

After my doctoral thesis I would have liked to continue with my research, but the lack of funding pushed me to explore other fields. Thanks to one of our collaborators, Dr. Ibai Diez Palacio, my work today is focused on the development of new therapies for Alzheimer disease. In the future, my goal is to obtain a postdoctoral grant to expand my knowledge and learn new techniques, with the hope of returning to the area of OI, as there are still many questions to be answered.

Tell us about your PhD project! Who was behind it?

My thesis was co-directed by Dr. Clara I. Rodríguez and Dr. Arantza Infante. This co-direction was crucial to the research’s success, as both directors worked closely to achieve our objectives. While Dr. Rodríguez provided guidance during the thesis, Dr. Infante also played a very important role.

Dr. Infante trained me and monitored my progress daily. She taught me how to ask the right research questions and most of the laboratory techniques. She also taught me to be more critical with the obtained results, in order to increase the quality of our findings.

Who financed the research?

The research has been funded by several institutions such as the Basque Government, the Carlos III Health Institute and the Mutua Madrileña Foundation. Furthermore, the research was also financed by the AHUCE foundation.

Who were the collaborators?

We had collaborators specialized in different areas during the research: Dr. Ana M Bueno, Dr. Belén Sagastizabal, Dr. Maitane Arroyo (all clinicians); Dr. Ainara Campino (pharmacist); Dr. Eider Sansebastian (chemist); and Dr. Daniela Gerovska, Dr. Marcos Araúzo-Bravo and Dr. Javier Aldazabal (engineers).

Moreover, during my thesis I completed an international stay in the University of Missouri (Columbia, MO, USA). There, Prof. Charlotte L. Phillips, alongside Dr. Lafaver and Dr. Crawford, trained me in different areas of OI. I learned how to work with a specific murine model of OI and to study the microarchitecture of murine bones, among others.

What were the main challenges/obstacles?

The main challenge of my thesis was to unify all the results obtained. I worked with a wide variety of cell lines from patients with OI, which were quite different from one another.

Additionally, as expected due to their heterogeneity, some of the mice responded differently to the drugs we were testing, hence it was a challenge to evaluate the effect of the therapy. In addition, working with OI murine models in vivo presented its own difficulties. Because of their fragility and my initial lack of experience, I had to learn how to carefully handle them to prevent fractures.

What was your research project about?

My research project was focused on the development of novel pharmacological therapies for OI. To do this, I used OI patient-derived mesenchymal stem cells (OI-MSCs) and animal models that recapitulate the key features of the disease.

The main strength of the project was the extensive collection of OI-MSCs used, which gave us a strong indication of how patients with different mutations might respond to distinct therapies. The primary limitations were the high heterogeneity of the cell lines, as well as the significant number of animals needed for in vivo studies. This was a direct result of the animals’ susceptibility to fractures, which complicated handling and data collection.

What were your most interesting or surprising findings?

Through this project we demonstrated that OI-MSCs are a valuable tool for identifying candidate molecules to treat OI. Furthermore, the findings from this study highlight the potential of three molecules for OI treatment: Galunisertib (a TGFbeta pathway modulator), G04 and E10 (two new small molecules). These molecules can modulate the differentiation of OI-MSCs, as well as improve bone properties in OI murine models. Interestingly, the beneficial effects obtained are dependent on dose, genotype, phenotype and sex.

Some of your research evolves around TGFbeta. This is a buzz word, but perhaps hard for people without science background to understand. Can you explain it in simple words?

TGF-beta is a protein that acts as a messenger in our body, telling cells what to do. While these signals are crucial for keeping us healthy, if the messaging system gets disrupted, it can contribute to disease. In fact, in some cases of OI, TGF-beta pathway becomes overactive leading to an altered phenotype. Subsequently, our research and that of others, is looking for novel therapies that can effectively quiet down the overactive signalling to restore the normal behaviour of the cells.

What kind of drug/compound is Galunisertib and do you think it has a future in OI?

Galunisertib is a small molecule able to inhibit the TGF-beta pathway. Its effect has been demonstrated in multiple trials as an anti-fibrotic and antineoplastic drug. In patients with OI, other different molecules that also inhibit the TGF-beta pathway (such as the monoclonal antibody Fresolimumab), have demonstrated encouraging results.

Compared to monoclonal antibodies, the fact that Galunisertib is a small molecule, offers several advantages. These include lower production cost, higher bone tissue permeability and a shorter half-life, among other things. Therefore, both monoclonal antibodies and small molecules could be different approaches to inhibit TGF-β pathway, each with its own set of advantages and disadvantages. That is why I believe that Galunisertib can have a promising future in OI.

And in which ways can stem cells play a role in OI?

Stem cells are proving to be a key player in OI research in two main ways. On one hand, stem cells, specifically those derived from OI patients (OI-MSCs) are an invaluable platform. They allow us to study the disease in a dish, screen for new drugs, and test the effectiveness of potential therapies on a patient-specific level. On the other hand, healthy mesenchymal stem cells and their derivatives are showing their potential as advanced therapies to restore the altered phenotype.

What is the most important take home message for clinical work?

The most important take-home message for clinical work is the critical need for a patient-centric and highly precise approach to developing new therapies. Given the significant heterogeneity of OI, it is essential to carefully select patients for clinical trials based on their specific disease characteristics and in vitro response.

This will ensure that the therapies being tested have the best chance of success for the intended population. Furthermore, a rigorous scientific process is non-negotiable. This involves preclinical validation of drugs and the use of the most appropriate animal models for each specific case.

Did you have patient involvement in your project?

Yes, patient involvement was a critical component of our research. We worked very closely with the AHUCE foundation, whose support and collaboration was absolutely vital. Their contributions went far beyond financial support.

The foundation was instrumental in disseminating our research findings and helped us build a crucial network of clinical collaborators. This partnership allowed us to recruit patients who generously donated samples, which in turn enabled us to create a wide collection of patient-derived cell lines, the very foundation of our work.

Thanks to our close collaboration, we gained a clear understanding of the real-world challenges faced by patients with OI. This direct insight has been invaluable, as it allows us to focus our research on addressing their most pressing concerns and working toward solutions that truly matter.

What do you do when you don’t do OI research?

When I am not thinking about OI, I have problems to slow down. I have played handball in my hometown’s club (Urduliz) for almost 20 years. Moreover, 2 years ago I started playing rugby, a sport that captivated me from the first day. Last year I had the opportunity to debut in the Women’s First Division of Rugby in Spain (Liga Iberdrola de Rugby). I also like traveling, walking, being with my family, and going out with friends. But when I need to relax, I love reading and lying on the beach.

Any messages for the readers of the OIFE Magazine?

Thank you for sharing so many experiences and updates. It is really motivating to see how families and adults with OI are involved in research. It is vital to highlight the importance of collaboration between researchers, doctors, patients and families.