Stem Cells and cell therapy (TERCELOI Project)
In OIFE Magazine 2-2023, we interviewed Clara I. Rodríguez who is the group leader of Stem cells and Cell therapy laboratory at Biocruces Bizkaia Health Research Institute in Bilbao, Spain.
Our laboratory focuses on the potential of human stem cells and their derivatives for the study of diseases and the development of new therapeutic strategies. The main research line of the lab is centered on the development of new efficient therapies for OI. We are developing several projects based on drug screening and repurposing in addition to the development of advanced therapy approaches. It is in relation to the latter that we have conducted a phase I cell therapy clinical trial (code: TERCELOI), demonstrating the safety and therapeutic potential of reiterative infusions of histocompatible BM-MSCs, in two OI pediatric patients. TERCELOI resulted in a decrease in the number of fractures, an improvement in bone parameters and the quality of life of the patients. The study of the mechanism of action indicated that MSCs therapy elicited a functional pro-osteogenic paracrine response in TERCELOI patients.
Tell us about the TERCELOI project!
The TERCELOI clinical trial as well as the cell mechanism of action studies was funded by the Spanish Ministry of Health through the call for independent clinical trials projects “EC10-219,” Instituto de Salud Carlos III through the project “PI15/00820” (Cofunded by European Regional Development Fund; “A way to make Europe”), local crowdfunding: (Bioef-EiTB maratoia (BIO14/TP/007), and the AHUCE Foundation.
What was your research project about?
Mesenchymal stem cells (MSCs), as the progenitors of the osteoblasts, the main type I collagen secreting cell type in the bone, have been proposed and tested as an innovative therapy for OI with promising but transient outcomes.
The rationale for this approach was that after transplantation, the MSCs as the progenitors of osteoblasts, would engraft in host tissues, differentiate into functional osteoblasts, and secrete normal collagen type I. This would ameliorate the symptoms associated with OI, as has been previously suggested by the identification of mosaic individuals demonstrating that high proportions of mutant osteoblasts (carrying OI mutation) are compatible with normal skeletal function.
Notably, the first cell therapy clinical trials were carried out by Horwitz and collaborators, in which, after cell therapy (1 or 2 MSCs infusions) OI pediatric patients showed improvements in terms of growth velocity and fracture frequency, but these beneficial effects were transitory and the expected cell engraftment into bone tissue was anecdotal. It is worth to mention that these first clinical trials were performed in breastfed children affected by severe OI, who were previously subjected to immunosuppression. The detailed mechanisms underlying these beneficial effects of MSCs therapy in OI are still unclear, but given the low engraftment achieved in cell therapy clinical trials applied to OI, the possibility of a paracrine therapeutic effect of MSCs is gaining attention.
To overcome the short-term effect of MSCs-therapy and to avoid subjecting the patients to an immunosuppression process, we performed a phase I cell therapy clinical trial based on five infusions of histocompatible MSCs, in two pediatric patients affected by severe (patient P01) and moderate (patient P02) OI (code: TERCELOI). The aim of TERCELOI was to assess the safety and effectiveness of five MSCs infusions along 2 years in non-immunosuppressed OI pediatric patients. Besides, the host response to MSCs was studied by analyzing the sera from OI patients, collected before, during and after the cell therapy.
We first demonstrated that the sequential administration of MSCs was safe in both patients (five infusions each patient).
• Reduced the number the fractures (see annexes, figure A). Thus, in accordance with their severe (P01) and moderate (P02) OI, both patients had a significant number of reported fractures from birth and through childhood: 15 in the case of P01 and 11 in the case of P02. During the year prior to MSCs therapy, P01 had 8 more documented fractures, and P02 had 2. Remarkably, during the 2.5 years of cell treatment, P01 showed a reduction in the number of fractures (3 documented fractures), whereas P02 reported only 2 fractures. Moreover, this effect was maintained in both patients until the end of the follow-up visits (one and two years after the fifth and last cellular infusion).
• Increased mobility, improved the bone parameters, and quality of life of OI patients along the cell treatment plus 2 years follow-up period.
Moreover, the study of the mechanism of action, indicated that MSCs therapy elicited a functional pro-osteogenic paracrine response in the TERCELOI patients, especially noticeable in the patient affected by severe OI (patient P01), demonstrating its functional capabilities. A major finding of our study, from a mechanistic point of view, is the existence of a systemic functional pro-osteogenic response in OI patients as a consequence of MSCs therapy.
What is the most important take home message for clinical work?
For a laboratory researcher like me, it has been incredible to work so closely with the clinicians involved in the daily care of OI patients. I choose as the most important lesson I learned from this experience is that clinical and research work should move hand in hand to figure out the best way to improve the quality of life of the OI patients and their families.
Were patients/patient organizations involved?
It had been inconceivable to carry out the clinical trial TERCELOI without the involvement, support and trust of the patients and their families. The Spanish OI organization AHUCE was crucial to contact and recruit the candidate families along the country, in addition to financially contributing to this work. Five families met the initial criteria to perform the histocompatibility analysis (that consists of checking the immunologic similarity in blood samples) between the patient (children >6 months and <12 years old) and their healthy siblings. Eventually only two patients could be included in the clinical trial. The participation of the healthy siblings with the bone marrow donation was absolutely courageous, and the engagement and joyfulness of the young patients was inspiring during the whole process. I would like to express my deepest gratitude.
Stem cell therapy is regarded as an advanced therapy medicinal products (ATMP) – are there any special challenges regarding access to these therapies for patients?
TERCELOI patients’ treatment required the donation of bone marrow-MSCs from an histocompatible sibling, which implied the need to have a healthy histocompatible sibling to donate stem cells. Not all pediatric OI patients who were able to benefit from this therapy possess a histocompatible donor, which definitely restricts their access to this therapy. In this regard and given the encouraging clinical and molecular outcomes of the TERCELOI clinical trial, we hope to increase the effectiveness of the cell therapy and to make it available to a larger number of patients without the need for a histocompatible donor. Our laboratory is working on a new line of research focused on the therapeutic potential of MSCs derivatives, such as the extracellular vesicles (EVs), which in addition of avoiding the need for a histocompatible donor, provide an abundant source of medicine, able to being repeatedly administered, and can be enriched to increase their effectiveness.
You can read the articles about the project here: