Arantza Infante1, Blanca Gener1,2, Miguel Vázquez3, Nerea Olivares4, Arantza Arrieta4, Gema Grau3, Isabel Llano2, Luis Madero5, Ana Maria Bueno6, Belén Sagastizabal7, Daniela Gerovska8, Marcos J Araúzo-Bravo8, Itziar Astigarraga3,9, Clara I Rodríguez1. 1. Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo, Spain. 2. Service of Genetics, Cruces University Hospital, Barakaldo, Spain. 3. Department of Pediatrics, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo, Spain. 4. Department of Biochemistry, Immunology Unit, Cruces University Hospital, Barakaldo, Spain. 5. Department of Pediatric Hematology, Oncology and Stem Cells, Niño Jesús University Children´s Hospital, Madrid, Spain. 6. Department of Orthopedic Surgery, Getafe University Hospital, Madrid, Spain. 7. Department of Endocrinology, Getafe University Hospital, Madrid, Spain. 8. Computational Biology and Systems Biomedicine Research Group, Biodonostia Health Research Institute, Donostia, Spain. 9. Department of Pediatrics, Basque Country University UPV/EHU, Leioa, Spain.
Abstract
BACKGROUND: Osteogenesis imperfecta (OI) is a rare genetic disease characterized by bone fragility, with a wide range in the severity of clinical manifestations. The majority of cases are due to mutations in the COL1A1 or COL1A2 genes, which encode type I collagen. 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. METHODS: To overcome the short-term effect of MSCs therapy, we performed a phase I clinical trial based on reiterative infusions of histocompatible MSCs, administered in a 2.5-year period, in two pediatric patients affected by severe and moderate OI. The aim of this study was to assess the safety and effectiveness of this cell therapy in nonimmunosuppressed OI patients. The host response to MSCs was studied by analyzing the sera from OI patients, collected before, during, and after the cell therapy. RESULTS: We first demonstrated that the sequential administration of MSCs was safe and improved the bone parameters and quality of life of OI patients along the cell treatment plus 2-year follow-up period. Moreover, the study of the mechanism of action indicated that MSCs therapy elicited a pro-osteogenic paracrine response in patients, especially noticeable in the patient affected by severe OI. CONCLUSIONS: Our results demonstrate the feasibility and potential of reiterative MSCs infusion for two pediatric OI and highlight the paracrine response shown by patients as a consequence of MSCs treatment.
BACKGROUND: Osteogenesis imperfecta (OI) is a rare genetic disease characterized by bone fragility, with a wide range in the severity of clinical manifestations. The majority of cases are due to mutations in the COL1A1 or COL1A2 genes, which encode type I collagen. 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. METHODS: To overcome the short-term effect of MSCs therapy, we performed a phase I clinical trial based on reiterative infusions of histocompatible MSCs, administered in a 2.5-year period, in two pediatric patients affected by severe and moderate OI. The aim of this study was to assess the safety and effectiveness of this cell therapy in nonimmunosuppressed OI patients. The host response to MSCs was studied by analyzing the sera from OI patients, collected before, during, and after the cell therapy. RESULTS: We first demonstrated that the sequential administration of MSCs was safe and improved the bone parameters and quality of life of OI patients along the cell treatment plus 2-year follow-up period. Moreover, the study of the mechanism of action indicated that MSCs therapy elicited a pro-osteogenic paracrine response in patients, especially noticeable in the patient affected by severe OI. CONCLUSIONS: Our results demonstrate the feasibility and potential of reiterative MSCs infusion for two pediatric OI and highlight the paracrine response shown by patients as a consequence of MSCs treatment.
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