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

Molecular Therapy

Volumn 22, Issue 5, 2014, Pages 901-907

  Torres Torronteras, Javier ^a,b   Viscomi, Carlo ^c,d   Cabrera Pérez, Raquel ^a,b   Cámara, Yolanda ^a,b   Di Meo, Ivano ^c   Barquinero, Jordi ^a   Auricchio, Alberto ^e   Pizzorno, Giuseppe ^f   Hirano, Michio ^g   Zeviani, Massimo ^c,d   Martí, Ramon ^a,b  

^a UNIVERSITAT AUTÒNOMA DE BARCELONA   (Spain)

^b INSTITUTO DE SALUD CARLOS III   (Spain)

^c DEPARTMENT OF NEUROSURGERY   (Italy)

^d UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^e UNIVERSITY OF NAPLES FEDERICO II   (Italy)

^f Desert Research Institute   (United States)

^g NewYork Presbyterian Hospital   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DEOXYCYTIDINE TRIPHOSPHATE; GENE THERAPY AGENT; MITOCHONDRIAL DNA; NUCLEOSIDE; NUCLEOTIDE; PARVOVIRUS VECTOR; TYMP PROTEIN; UNCLASSIFIED DRUG; THYMIDINE; THYMIDINE PHOSPHORYLASE; TYMP PROTEIN, HUMAN;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DNA REPLICATION; DRUG EFFECT; DRUG SAFETY; GENE; GENE EXPRESSION; GENE TARGETING; GENE TRANSFER; HOMEOSTASIS; MALE; MITOCHONDRIAL RESPIRATION; MNGIE SYNDROME; MOUSE; NONHUMAN; NUCLEOTIDE METABOLISM; PROMOTER REGION; TRANSGENE; TYMP GENE; VIRAL GENE THERAPY; ANIMAL; BIOSYNTHESIS; DEPENDOPARVOVIRUS; DISEASE MODEL; GENE THERAPY; GENE VECTOR; GENETICS; HUMAN; INTESTINAL PSEUDO-OBSTRUCTION; LIVER; METABOLISM; MITOCHONDRIAL ENCEPHALOMYOPATHIES; MUTATION; PATHOLOGY;

MURINAE; MUS;

ANIMALS; DEPENDOVIRUS; DISEASE MODELS, ANIMAL; DNA, MITOCHONDRIAL; GENETIC THERAPY; GENETIC VECTORS; HOMEOSTASIS; HUMANS; INTESTINAL PSEUDO-OBSTRUCTION; LIVER; MICE; MITOCHONDRIAL ENCEPHALOMYOPATHIES; MUTATION; THYMIDINE; THYMIDINE PHOSPHORYLASE;

EID: 84899994577     PISSN: 15250016     EISSN: 15250024     Source Type: Journal    
DOI: 10.1038/mt.2014.6     Document Type: Article

References (33)

1. Garone, C, Tadesse, S and Hirano, M (2011). Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy. Brain 134(Pt 11): 3326-3332.
2. Nishino, I, Spinazzola, A and Hirano, M (1999). Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 283: 689-692.
3. Martí, R, Nishigaki, Y and Hirano, M (2003). Elevated plasma deoxyuridine in patients with thymidine phosphorylase deficiency. Biochem Biophys Res Commun 303: 14-18.
4. Pontarin, G, Ferraro, P, Valentino, ML, Hirano, M, Reichard, P and Bianchi, V (2006). Mitochondrial DNA depletion and thymidine phosphate pool dynamics in a cellular model of mitochondrial neurogastrointestinal encephalomyopathy. J Biol Chem 281: 22720-22728.
5. López, LC, Akman, HO, García-Cazorla, A, Dorado, B, Martí, R, Nishino, I et al. (2009). Unbalanced deoxynucleotide pools cause mitochondrial DNA instability in thymidine phosphorylase-deficient mice. Hum Mol Genet 18: 714-722.
6. González-Vioque, E, Torres-Torronteras, J, Andreu, AL and Martí, R (2011). Limited dCTP availability accounts for mitochondrial DNA depletion in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). PLoS Genet 7: e1002035.
7. Yavuz, H, Ozel, A, Christensen, M, Christensen, E, Schwartz, M, Elmaci, M et al. (2007). Treatment of mitochondrial neurogastrointestinal encephalomyopathy with dialysis. Arch Neurol 64: 435-438.
8. Spinazzola, A, Marti, R, Nishino, I, Andreu, AL, Naini, A, Tadesse, S et al. (2002). Altered thymidine metabolism due to defects of thymidine phosphorylase. J Biol Chem 277: 4128-4133.
9. Moran, NF, Bain, MD, Muqit, MM and Bax, BE (2008). Carrier erythrocyte entrapped thymidine phosphorylase therapy for MNGIE. Neurology 71: 686-688.
10. Lara, MC, Weiss, B, Illa, I, Madoz, P, Massuet, L, Andreu, AL et al. (2006). Infusion of platelets transiently reduces nucleoside overload in MNGIE. Neurology 67: 1461-1463.
11. Hirano, M, Martí, R, Casali, C, Tadesse, S, Uldrick, T, Fine, B et al. (2006). Allogeneic stem cell transplantation corrects biochemical derangements in MNGIE. Neurology 67: 1458-1460.
12. Halter, J, Schüpbach, WM, Casali, C, Elhasid, R, Fay, K, Hammans, S et al. (2011). Allogeneic hematopoietic SCT as treatment option for patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a consensus conference proposal for a standardized approach. Bone Marrow Transplant 46: 330-337.
13. Torres-Torronteras, J, Gómez, A, Eixarch, H, Palenzuela, L, Pizzorno, G, Hirano, M et al. (2011). Hematopoietic gene therapy restores thymidine phosphorylase activity in a cell culture and a murine model of MNGIE. Gene Ther 18: 795-806.
14. Smith, RH (2008). Adeno-associated virus integration: virus versus vector. Gene Ther 15: 817-822.
15. Nathwani, AC, Tuddenham, EG, Rangarajan, S, Rosales, C, McIntosh, J, Linch, DC et al. (2011). Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 365: 2357-2365.
16. Di Meo, I, Auricchio, A, Lamperti, C, Burlina, A, Viscomi, C and Zeviani, M (2012). Effective AAV-mediated gene therapy in a mouse model of ethylmalonic encephalopathy. EMBO Mol Med 4: 1008-1014.
17. Kong, W, Engel, K and Wang, J (2004). Mammalian nucleoside transporters. Curr Drug Metab 5: 63-84.
18. Stein, S, Ott, MG, Schultze-Strasser, S, Jauch, A, Burwinkel, B, Kinner, A et al. (2010). Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nat Med 16: 198-204.
19. Hacein-Bey-Abina, S, Von Kalle, C, Schmidt, M, McCormack, MP, Wulffraat, N, Leboulch, P et al. (2003). LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302: 415-419.
20. Nakai, H, Iwaki, Y, Kay, MA and Couto, LB (1999). Isolation of recombinant adeno-associated virus vector-cellular DNA junctions from mouse liver. J Virol 73: 5438-5447.
21. Kearns, WG, Afione, SA, Fulmer, SB, Pang, MC, Erikson, D, Egan, M et al. (1996). Recombinant adeno-associated virus (AAV-CFTR) vectors do not integrate in a sitespecific fashion in an immortalized epithelial cell line. Gene Ther 3: 748-755.
22. Flotte, TR, Afione, SA and Zeitlin, PL (1994). Adeno-associated virus vector gene expression occurs in nondividing cells in the absence of vector DNA integration. Am J Respir Cell Mol Biol 11: 517-521.
23. Donsante, A, Vogler, C, Muzyczka, N, Crawford, JM, Barker, J, Flotte, T et al. (2001). Observed incidence of tumorigenesis in long-term rodent studies of rAAV vectors. Gene Ther 8: 1343-1346.
24. Gauttier, V, Pichard, V, Aubert, D, Kaeppel, C, Schmidt, M, Ferry, N et al. (2013). No tumour-initiating risk associated with scAAV transduction in newborn rat liver. Gene Ther 20: 779-784.
25. Zincarelli, C, Soltys, S, Rengo, G and Rabinowitz, JE (2008). Analysis of AAV serotypes 1-9 mediated gene expression and tropism in mice after systemic injection. Mol Ther 16: 1073-1080.
26. Tessitore, A, Faella, A, O'Malley, T, Cotugno, G, Doria, M, Kunieda, T et al. (2008). Biochemical, pathological, and skeletal improvement of mucopolysaccharidosis VI after gene transfer to liver but not to muscle. Mol Ther 16: 30-37.
27. Nathwani, AC, Gray, JT, Ng, CY, Zhou, J, Spence, Y, Waddington, SN et al. (2006). Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver. Blood 107: 2653-2661.
28. Xiao, W, Chirmule, N, Berta, SC, McCullough, B, Gao, G and Wilson, JM (1999). Gene therapy vectors based on adeno-associated virus type J Virol 73: 3994-4003.
29. Gao, G, Qu, G, Burnham, MS, Huang, J, Chirmule, N, Joshi, B et al. (2000). Purification of recombinant adeno-associated virus vectors by column chromatography and its performance in vivo. Hum Gene Ther 11: 2079-2091.
30. Bradford, MM (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248-254.
31. Valentino, ML, Martí, R, Tadesse, S, López, LC, Manes, JL, Lyzak, J et al. (2007). Thymidine and deoxyuridine accumulate in tissues of patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). FEBS Lett 581: 3410-3414.
32. Medja, F, Allouche, S, Frachon, P, Jardel, C, Malgat, M, Mousson de Camaret, B et al. (2009). Development and implementation of standardized respiratory chain spectrophotometric assays for clinical diagnosis. Mitochondrion 9: 331-339.
33. Graham, JM (2001). Purification of a crude mitochondrial fraction by density-gradient centrifugation. Curr Protoc Cell Biol Chapter 3: Unit 34.