Open AccessLong-Term Sustained Effect of Liver-Targeted Adeno-Associated Virus Gene Therapy for Mitochondrial Neurogastrointestinal Encephalomyopathy
Author(s) -
Javier TorresTorronteras,
Raquel Cabrera-Pérez,
Ferran Vila-Julià,
Carlo Viscomi,
Yolanda Cámara,
Michio Hirano,
Massimo Zeviani,
Ramón Martí
Publication year - 2018
Publication title -
human gene therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.633
H-Index - 149
eISSN - 1557-7422
pISSN - 1043-0342
DOI - 10.1089/hum.2017.133
Subject(s) - thymidine phosphorylase , genetic enhancement , biology , viral vector , adeno associated virus , cancer research , vector (molecular biology) , gene , nucleoside , deoxyuridine , medicine , microbiology and biotechnology , cancer , genetics , dna , recombinant dna
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by mutations in TYMP, the gene encoding the enzyme thymidine phosphorylase (TP). TP dysfunction results in systemic accumulation of the noxious TP substrates thymidine and deoxyuridine. Gene therapy using either a lentiviral vector or adeno-associated vector (AAV) has proven to be a feasible strategy, as both vectors restore biochemical homeostasis in a murine model of the disease. This study shows that the effect of an AAV containing the TYMP coding sequence transcriptionally targeted to the liver persists long term in mice. Although the vector copy number was diluted and AAV-mediated liver TP activity eventually reduced or lost after 21 months at the lowest vector doses, the effect was sustained (with a negligible decrease in TP activity) and fully effective on nucleoside homeostasis for at least 21 months at a dose of 2 × 10 12 vg/kg. Macroscopic visual inspection of the animals' organs at completion of the study showed no adverse effects associated with the treatment. These results further support the feasibility of gene therapy for MNGIE.