Gene therapy using a liver-targeted AAV vector restores nucleoside and nucleotide homeostasis in a murine model of MNGIE.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in TYMP, enconding thymidine phosphorylase (TP). TP deficiency results in systemic accumulation of thymidine and deoxyuridine, which interferes with mitochondrial DNA (mtDNA) replication and leads to mitochondrial dysfunction. To date, the only treatment available for MNGIE patients is allogeneic hematopoietic stem cell transplantation, which is associated with high morbidity and mortality. Here, we report that AAV2/8-mediated transfer of the human TYMP coding sequence (hcTYMP) under the control of a liver-specific promoter prevents the biochemical imbalances in a murine model of MNGIE. hcTYMP expression was restricted to liver, and a dose as low as 2 × 10(11) genome copies/kg led to a permanent reduction in systemic nucleoside levels to normal values in about 50% of treated mice. Higher doses resulted in reductions to normal or slightly below normal levels in virtually all mice treated. The nucleoside reduction achieved by this treatment prevented deoxycytidine triphosphate (dCTP) depletion, which is the limiting factor affecting mtDNA replication in this disease. These results demonstrate that the use of AAV to direct TYMP expression in liver is feasible as a potentially safe gene therapy strategy for MNGIE.
1] Mitochondrial Disorders Unit, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain; [2] Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain;
Javier
J
Torres-Torronteras
1] Molecular Neurogenetics Unit, IRCCS Foundation Neurological Institute "C, Besta", Milan, Italy; [2] MRC-Mitochondrial Biology Unit, Cambridge, UK;
Carlo
C
Viscomi
1] Mitochondrial Disorders Unit, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain; [2] Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain;
Raquel
R
Cabrera-Pérez
1] Mitochondrial Disorders Unit, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain; [2] Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain;
Yolanda
Y
Cámara
Molecular Neurogenetics Unit, IRCCS Foundation Neurological Institute "C, Besta", Milan, Italy;
Ivano
I
Di Meo
Gene and Cell Therapy Unit, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain;
Jordi
J
Barquinero
Telethon Institute of Genetics and Medicine and Division of Medical Genetics, Department of Pediatrics, ''Federico II'' University, Naples, Italy;
Alberto
A
Auricchio
Human Health and Environment Program, Desert Research Institute, Las Vegas, Nevada, USA;
Giuseppe
G
Pizzorno
Department of Neurology, Columbia University Medical Center, New York, USA.
Michio
M
Hirano
1] Molecular Neurogenetics Unit, IRCCS Foundation Neurological Institute "C, Besta", Milan, Italy; [2] MRC-Mitochondrial Biology Unit, Cambridge, UK;
Massimo
M
Zeviani
1] Mitochondrial Disorders Unit, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain; [2] Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain;
Ramon
R
Martí
D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007418:Intestinal Pseudo-Obstruction / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D008099:Liver / Q000378:metabolism; D051379:Mice; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D039141:Muscular Dystrophy, Oculopharyngeal; D009154:Mutation; D009886:Ophthalmoplegia / Q000151:congenital; D013936:Thymidine / Q000378:metabolism; D013939:Thymidine Phosphorylase / Q000096:biosynthesis / Q000235:genetics*; D028361:Mitochondrial Diseases
D004272:DNA, Mitochondrial; C543750:TYMP protein, human; D013939:Thymidine Phosphorylase; D013936:Thymidine