Advanced therapies – cell & animal models for OI
Interview with Lida Zhytnik, member of OIFE Medical Advisory Board
We have already interviewed you before Lida, but can you tell us what you have been up to since last time?
The last couple of years were very active, challenging, but at the same time the most interesting years for me. I moved to the Netherlands. I finally got an opportunity to broaden my research experience with basic research, as previously I was more involved more in translational projects. And I am very happy that now I can combine both directions in my work.
I am very grateful for this opportunity given to me by my colleagues Dr. Dimitra Micha and Prof. Elisabeth Marelise Eekhoff from Amsterdam UMC. They believed in me and allowed me to join their team and learn from them, even though I lacked basic research experience at that moment and had to learn a lot.
You finished your postdoc project in May 2024 – tell us about the project: What were your most interesting findings and conclusions?
The project “THOR-OI” (Therapy for OI), was supported by the Estonian Research Council (grant PUTJD1009), and lasted from 2021 to 2024. During these three years I joined the Amsterdam UMC, Department of Human Genetics, Centre for Connective Tissue Disorders, with PI Dr Dimitra Micha. Together we developed advanced therapies for OI and created cell-and animal models for OI.
One of the challenges in preclinical OI research has been the lack of a reliable mouse model for patients with the most classical OI type 1, which affects at least one third of all OI people. This fact is pretty striking, as there are at least 20 different mouse models for the different OI genes. However, there are none for haploinsufficient COL1A1 OI, which is a very prevalent OI type.
This gap was obviously slowing down the development of new treatments, and understanding of OI type I. The existing mouse model Mov13 that was created in 80-s develops leukemia, and cannot be used for research, including testing of therapies. In the Netherlands it is even not allowed to house these animals. Within the project we have developed a new mouse model that mimics the mild form of OI – the haploinsufficient* OI (hiOI) mouse. These mice have brittle bones, less collagen type I and extraskeletal features, similar to humans with OI type I. The hiOI mice will finally allow us to move forward with preclinical therapy testing – also for type I OI.
Another exciting development of the project is progress in gene therapy for OI. Treating the skeleton is particularly challenging because it is a complex organ system, and OI is caused by many different genetic defects, requiring personalized approaches for each patient.
Our team created special stem cells from the skin of OI patients that can turn into bone-forming cells. These stem cells can build bone in lab dishes and in mice. Using a technique called CRISPR-Cas, these cells were genetically edited to correct the defect causing OI.
The project showed that this is the first step towards the desired approach of making corrected stem cells which could be potentially reintroduced into humans to produce healthy collagen. The method still needs fine-tuning, but we are happy with first milestones.
Another method for gene therapy involves directly editing the genes inside the patient’s body (in vivo gene therapy). There are couple of approved EMA products based on that technology for diseases of other organ systems. We tested a specialized technology of healthy collagen gene delivery on new OI cell models, offering a new approach to treating OI with AAV virus. And I am very proud to say, that the results from studies are very promising. We are currently trying to raise enough funds to continue the project.
*Haploinsufficient describes a situation in which the total level of a gene product (a particular protein) produced by the cell is about half of the normal level and that is not sufficient.
Are there any take home messages for clinical work?
The patient community has kept saying that mild OI (type I) is not always mild, for many years. I agree 100% with this view. OI type I is not a “mild” version of OI type 3. It’s a very different mechanism of the disorder, and we have to study it more. I hope that the OI mice will help us with doing this.
How can we improve the collaboration between basic scientists and clinicians?
How can we improve the collaboration between basic scientists and clinicians?My personal opinion is that in every collaboration the key ingredient is people. I adore those clinical professionals, who are research-oriented, proactive, seek collaboration, creative with their ideas, and who are not afraid to deep-dive into basic science. And at the same time, I am very thankful to basic researchers who go out of the lab, talk to clinicians and patients, and orient their research to serve patient needs, not only their scientific interests.
I was very lucky, as I have always worked closely with clinical professionals, and I have never lacked support from the clinical side. During my PhD in University of Tartu, I worked with excellent the orthopaedic surgeons Dr. Katre Maasalu and Prof. Aare Märtson, who were always goal-oriented, confident, decisive and hard-working. Thanks to their passion and interest in research, we completed amazing projects, and this collaboration still continues.
And in Amsterdam UMC I saw an inspiring example of collaboration between basic and clinical researchers. It’s the team of Dr. Micha and Prof Eekhoff, who work closely together. It’s very satisfying to see how the worlds of preclinical and clinical research synergistically come together in the Rare Bone Disease centre. It’s much more than sharing of samples, and interpreting results of studies. They think together, develop new ideas and research lines and they educate the new generation of professionals.
It was also new for me, that when preclinical and clinical researchers collaborate this close, patients can also be very actively involved in the whole process. In Amsterdam I could experience, that the patient is the centre of the treatment process and research, which is extremely important for a rare condition like OI.
Can you mention any challenges or highlights during the process?
Research is always like a roller-coaster with ups and down. But in the end, this is what makes you attached to it. I think that one of the biggest challenges is to learn how to accept and live through the “downs”. Negative results of the experiments, grant rejections, publications that are declined. I try to focus on gaining experience from these “downs” and adapt to finding new ways to make it work and reach the goal.
I also feel that there is a lack of transparency in data even if there are many initiatives to change this in the scientific community. I hope that this will slowly progress. It is also extremely important to have your “support team” of colleagues and friends, with whom you can share, and who understand you and have same values. I was very privileged to find these people in my professional career, as well as my mentors from the OI community.
We heard that you won a prestigious award – tell us about your plans for the coming two years!
Yes, and it was amazing. It is really getting harder and harder to find funding resources for research with the global economic crisis which we are currently living in. I therefore think I was very lucky to get a Marie-Skladowska Curie Actions (MSCA) Postdoctoral Fellowship to join the research team of Prof. Ivan Duran (photo) in University of Malaga and IBIMA-Bionand and continue my work on gene therapy development for OI. Prof. Duran is an expert in tissue engineering, and I am very honoured to work the next 2 years in his lab.
In collaboration with Amsterdam UMC, we will continue the promising work and develop it further. We will create bone organoids and advanced 3D cell cultures of special stem cells, which we have developed before.
The idea is to challenge them into growing into mini bones in the lab dishes, and then treat these mini OI bones with AAV viruses, to see if in vivo gene therapy would help to repair the genetic defect. I am very excited about this new stage of the project.
Although it is clear that the development of this technology for bone disorders will still take a long time, it is very important to make all these small steps further. Otherwise it will never happen. During the MSCA project I also plan to work more closely with OIFE and national patient associations on educational initiatives. I would like to make the OI community more knowledgeable about OI genetics and the concept of gene therapy.
Do you feel that having OI yourself gives you any advantages or challenges in OI research?
The biggest advantage for me, is that I do not feel that my job is an actual job. I am just very interested in OI – learning more about it and how it works – in all aspects of biology, physical and mental health and social life. It just feels like getting to know and understand myself more. If people want to make me interested in a topic, they just mention “OI” and I am in. Sometimes my personal experience gives advantages, as I can relate and find key connections, which might not be obvious at first.
Also, I see both worlds – research and patient – and understand both sides. It helps to bridge the communication to the benefit of both communities. I find this extremely important. Oh, and finally you always have some patient material with you.
And good that you ask about challenges. As I have OI, labwork is physically challenging during the “bad bone days”. Especially related to stem cells, which need to be treated daily. I would like to thank my lab-besties Lauria Claeys and Laura Ventura for their understanding, support and everyday help.
It also can be mentally overwhelming from time to time to always deal with the “OI topic”. With work, volunteering for patient organizations, my family and also myself. It is therefore nice, to have some other hobbies or activities, which help to switch off and distract.
Clinical and basic science research are two fundamental branches of medical research. While clinical research focuses on the direct application of knowledge to improve patient care, basic science research delves into understanding the underlying mechanisms of diseases and biological processes.
What are the biggest knowledge gaps in OI research?
For the basic research, I guess it’s nice functional assays for human OI cell models, which would reliably reflect the affected phenotype. And I would be happy to see more preclinical studies on chronic pain in OI. This is a primary issue affecting the quality of life in adult age, and it would be great to know how to manage it more effectively.
What would be your dream project?
My dream project would be the development of gene therapy for other rare skeletal dysplasias. Meaning that if we succeeded in doing it in OI, I could switch to other diseases.
Any messages for the readers of OIFE Magazine?
Science is fun. I would be more than happy if we together could find a way to show the OI community that this is an important and exciting area of healthcare, as even the most basic science will lead to improvement of patient care in the future.
You can read the first interview we did with Lida here called “OI and reproduction”.
