Preclinical Efficacy and Safety Evaluation of Hematopoietic Stem Cell Gene Therapy in a Mouse Model of MNGIE

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by thymidine phosphorylase (TP) deficiency resulting in systemic accumulation of thymidine (d-Thd) and deoxyuridine (d-Urd) and characterized by early-onset neurological and gastrointestinal sympt...

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Detalles Bibliográficos
Autores: Yadak, Rana, Cabrera-Pérez, Raquel|||0000-0002-4858-0142, Torres-Torronteras, Javier|||0000-0002-6092-9458, Bugiani, Marianna, Haeck, Joost C., Huston, Marshall W., Bogaerts, Elly, Goffart, Steffi, Jacobs, Edwin H., Stok, Merel, Leonardelli, Lorena, Biasco, Luca, Verdijk, Robert M., Bernsen, Monique R., Ruijter, George, Martí, Ramon A.|||0000-0002-8273-9540, Wagemaker, Gerard, van Til, Niek P., de Coo, Irenaeus F. M.
Tipo de recurso: artículo
Fecha de publicación:2018
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:190792
Acceso en línea:https://ddd.uab.cat/record/190792
https://dx.doi.org/urn:doi:10.1016/j.omtm.2018.01.001
Access Level:acceso abierto
Palabra clave:MNGIE
Thymidine phosphorylase
Hematopoietic stem cells
Lentiviral vectors
Gene therapy
Descripción
Sumario:Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by thymidine phosphorylase (TP) deficiency resulting in systemic accumulation of thymidine (d-Thd) and deoxyuridine (d-Urd) and characterized by early-onset neurological and gastrointestinal symptoms. Long-term effective and safe treatment is not available. Allogeneic bone marrow transplantation may improve clinical manifestations but carries disease and transplant-related risks. In this study, lentiviral vector-based hematopoietic stem cell gene therapy (HSCGT) was performed in Tymp -/- Upp1 -/- mice with the human phosphoglycerate kinase (PGK) promoter driving TYMP. Supranormal blood TP activity reduced intestinal nucleoside levels significantly at low vector copy number (median, 1.3; range, 0.2-3.6). Furthermore, we covered two major issues not addressed before. First, we demonstrate aberrant morphology of brain astrocytes in areas of spongy degeneration, which was reversed by HSCGT. Second, long-term follow-up and vector integration site analysis were performed to assess safety of the therapeutic LV vectors in depth. This report confirms and supplements previous work on the efficacy of HSCGT in reducing the toxic metabolites in Tymp -/- Upp1 -/- mice, using a clinically applicable gene transfer vector and a highly efficient gene transfer method, and importantly demonstrates phenotypic correction with a favorable risk profile, warranting further development toward clinical implementation.

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