Preclinical Efficacy and Safety Evaluation of Hematopoietic Stem Cell Gene Therapy in a Mouse Model of MNGIE
Yadak, Rana (Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands)
Cabrera-Pérez, Raquel (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Torres-Torronteras, Javier (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Bugiani, Marianna (Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands)
Haeck, Joost C. (Department of Radiology & Nuclear Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands)
Huston, Marshall W. (Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands)
Bogaerts, Elly (Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands)
Goffart, Steffi (Department of Biology, University of Eastern Finland, Joensuu, Finland)
Jacobs, Edwin H. (Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands)
Stok, Merel (Department of Pediatrics, Erasmus University Medical Center, Rotterdam, the Netherlands)
Leonardelli, Lorena (San Raffaele Telethon Institute for Gene Therapy (Milà, Itàlia))
Biasco, Luca (University College of London (UCL), Great Ormond Street Institute of Child Health (ICH), London, UK)
Verdijk, Robert M. (Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands)
Bernsen, Monique R. (Department of Radiology & Nuclear Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands)
Ruijter, George (Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands)
Martí, Ramon A. (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Wagemaker, Gerard (Raisa Gorbacheva Memorial Research Institute for Pediatric Oncology and Hematology, Saint Petersburg, Russia)
van Til, Niek P. (Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands)
de Coo, Irenaeus F. M. (Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands)
Universitat Autònoma de Barcelona

Date:	2018
Abstract:	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.
Grants:	Instituto de Salud Carlos III 15-000465
Note:	Altres ajuts: The authors acknowledge the financial support for this study by Join4energy, Ride4Kids, the Sophia Foundation (SSW0645), Stichting NeMo, in the context of funding provided by the European Commission's 5th, 6th, and 7th Framework Programs(contracts QLK3-CT-2001-00427-INHERINET, LSHB-CT-2004-005242-CONSERT, LSHB-CT-2006-19038 Magselectofection, and grant agreements 222878-PERSIST and 261387 CELL-PID), and by the Netherlands Health Research and Development Organization ZonMw (Translational Gene Therapy program projects 43100016 and 43400010). We thank Dr. Michio Hirano (Department of Neurology, Columbia University Medical Center, New York, USA) for providing the murine model, Louis Boon (Epirus Biopharmaceuticals, Utrecht, the Netherlands) for kindly providing anti-B220 antibody, Prof. Peter A.E. Sillevis Smitt (Department of Neurology, Erasmus MC, Rotterdam, the Netherlands), Pier.G. Mastroberardino and Chiara Milanese (Department of Molecular Genetics, Erasmus MC), Kees Schoonderwoerd (Department of Clinical Genetics, Erasmus MC), and Jeroen de Vrij (Department of Neurosurgery, Erasmus MC) for valuable discussions, Lidia Hussaarts (Department of Clinical Genetics, Erasmus MC) for technical support, King Lam (Department of Pathology, Erasmus MC) for pathology evaluation, and F. Dionisio and A. Aiuti from HSR-TIGET, Milan, for the support to the integration site analysis.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	MNGIE ; Thymidine phosphorylase ; Hematopoietic stem cells ; Lentiviral vectors ; Gene therapy
Published in:	Molecular Therapy. Methods & Clinical Development, Vol. 8 (january 2018) , p. 152-165, ISSN 2329-0501

DOI: 10.1016/j.omtm.2018.01.001
PMID: 29687034

14 p, 2.3 MB

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