Gene therapy using a liver-targeted AAV vector restores nucleoside and nucleotide homeostasis in a murine model of MNGIE.

TitleGene therapy using a liver-targeted AAV vector restores nucleoside and nucleotide homeostasis in a murine model of MNGIE.
Publication TypeJournal Article
Year of Publication2014
AuthorsTorres-Torronteras, J, Viscomi, C, Cabrera-Pérez, R, Cámara, Y, Di Meo, I, Barquinero, J, Auricchio, A, Pizzorno, G, Hirano, M, Zeviani, M, Martí, R
JournalMol Ther
Date Published2014 May
KeywordsAnimals, Dependovirus, Disease Models, Animal, DNA, Mitochondrial, Genetic Therapy, Genetic Vectors, Homeostasis, Humans, Intestinal Pseudo-Obstruction, Liver, Mice, Mitochondrial Encephalomyopathies, Mutation, Thymidine, Thymidine Phosphorylase

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.

Alternate JournalMol. Ther.
Citation Key10.1038/mt.2014.6
PubMed ID24448160
PubMed Central IDPMC4015233
Grant ListGGP11011 / / Telethon / Italy
GPP10005 / / Telethon / Italy
MC_UP_1002/1 / / Medical Research Council / United Kingdom