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Tytuł pozycji:

Efficacy of adeno-associated virus gene therapy in a MNGIE murine model enhanced by chronic exposure to nucleosides.

Tytuł:
Efficacy of adeno-associated virus gene therapy in a MNGIE murine model enhanced by chronic exposure to nucleosides.
Autorzy:
Vila-Julià F; Research Group on Neuromuscular and Mitochondrial Diseases, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, and Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Catalonia, Spain.
Cabrera-Pérez R; Research Group on Neuromuscular and Mitochondrial Diseases, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, and Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Catalonia, Spain.
Cámara Y; Research Group on Neuromuscular and Mitochondrial Diseases, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, and Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Catalonia, Spain.
Molina-Berenguer M; Research Group on Neuromuscular and Mitochondrial Diseases, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, and Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Catalonia, Spain.
Lope-Piedrafita S; Servei de Ressonància Magnètica Nuclear, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Catalonia, Spain; Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Cerdanyola del Vallès, Catalonia, Spain.
Hirano M; Department of Neurology, H. Houston Merritt Neuromuscular Research Center, Columbia University Irving Medical Center, New York, NY, United States.
Mingozzi F; Spark Therapeutics, Philadelphia, PA 19104, United States.
Torres-Torronteras J; Research Group on Neuromuscular and Mitochondrial Diseases, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, and Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Catalonia, Spain. Electronic address: .
Martí R; Research Group on Neuromuscular and Mitochondrial Diseases, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, and Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Catalonia, Spain. Electronic address: .
Źródło:
EBioMedicine [EBioMedicine] 2020 Dec; Vol. 62, pp. 103133. Date of Electronic Publication: 2020 Nov 21.
Typ publikacji:
Journal Article
Język:
English
Imprint Name(s):
Original Publication: [Amsterdam] : Elsevier B.V., [2014]-
MeSH Terms:
Genetic Therapy*/methods
Dependovirus/*genetics
Genetic Vectors/*genetics
Intestinal Pseudo-Obstruction/*genetics
Intestinal Pseudo-Obstruction/*therapy
Muscular Dystrophy, Oculopharyngeal/*genetics
Muscular Dystrophy, Oculopharyngeal/*therapy
Nucleosides/*pharmacology
Ophthalmoplegia/*congenital
Animals ; Combined Modality Therapy ; Disease Models, Animal ; Enzyme Activation ; Gene Dosage ; Gene Expression ; Humans ; Liver/metabolism ; Mice ; Mice, Knockout ; Mitochondrial Diseases/genetics ; Mitochondrial Diseases/therapy ; Ophthalmoplegia/genetics ; Ophthalmoplegia/therapy ; Phenotype ; Thymidine Phosphorylase/genetics ; Treatment Outcome
Contributed Indexing:
Keywords: Gene therapy; MNGIE; Mitochondrial disease; Nucleosides; Thymidine phosphorylase
Substance Nomenclature:
0 (Nucleosides)
EC 2.4.2.4 (TYMP protein, human)
EC 2.4.2.4 (Thymidine Phosphorylase)
SCR Disease Name:
Visceral myopathy familial external ophthalmoplegia
Entry Date(s):
Date Created: 20201124 Date Completed: 20210824 Latest Revision: 20210824
Update Code:
20240105
PubMed Central ID:
PMC7689515
DOI:
10.1016/j.ebiom.2020.103133
PMID:
33232869
Czasopismo naukowe
Background: Preclinical studies have shown that gene therapy is a feasible approach to treat mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the genetic murine model of the disease (Tymp/Upp1 double knockout, dKO) has a limited functional phenotype beyond the metabolic imbalances, and so the studies showing efficacy of gene therapy have relied almost exclusively on demonstrating correction of the biochemical phenotype. Chronic oral administration of thymidine (dThd) and deoxyuridine (dUrd) to dKO mice deteriorates the phenotype of the animals, providing a better model to test therapy approaches.
Methods: dKO mice were treated with both dThd and dUrd in drinking water from weaning until the end of the study. At 8 - 11 weeks of age, mice were treated with several doses of adeno-associated virus (AAV) serotype 8 vector carrying the human TYMP coding sequence under the control of different liver-specific promoters (TBG, AAT, or HLP). The biochemical profile and functional phenotype were studied over the life of the animals.
Findings: Nucleoside exposure resulted in 30-fold higher plasma nucleoside levels in dKO mice compared with non-exposed wild type mice. AAV-treatment provided elevated TP activity in liver and lowered systemic nucleoside levels in exposed dKO mice. Exposed dKO mice had enlarged brain ventricles (assessed by magnetic resonance imaging) and motor impairment (rotarod test); both were prevented by AAV treatment. Among all promoters tested, AAT showed the best efficacy.
Interpretation: Our results show that AAV-mediated gene therapy restores the biochemical homeostasis in the murine model of MNGIE and, for the first time, demonstrate that this treatment improves the functional phenotype.
Funding: This work was funded in part by the Spanish Instituto de Salud Carlos III, and the Generalitat de Catalunya. The disclosed funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: Declaration of Competing Interests RM, FV and MM report grants from the Instituto de Salud Carlos III during the conduct of the study; JT reports grants from Departament de Salut, Generalitat de Catalunya (PERIS program), during the conduct of the study; RM, MH, JT and YC report grants and non-financial support from Modis Therapeutics, personal fees and other from Modis Therapeutics, outside the submitted work; in addition, RM and MH have a patent “Deoxynucleoside therapy for diseases caused by unbalanced nucleotide pools including mitochondrial DNA depletion syndromes” (PCT/US16/038110) with royalties paid to Modis Therapeutics; MH reports grants and other support from Entrada Therapeutics, grants from Muscular Dystrophy Association and grants from NIH, outside the submitted work; FM is an employee of Spark Therapeutics; SL reports that the Nuclear Magnetic Resonance facility where she works charged the VHIR a fee for the MRI services; and RM, YC, JT and RC have a patent “Treatment of mitochondrial diseases” (PCT/EP2016/062636) with royalties paid to Modis Therapeutics.
(Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

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