Summary
Mucopolysaccharidosis I (MPS I) is a lysosomal disorder characterized by a deficiency of the enzyme α-L-iduronidase (IDUA), which is responsible for the degradation of glycosaminoglycans (GAGs). This deficiency leads to the accumulation of dermatan and heparan sulphate in lysosomes. Presently available treatments include bone marrow transplantation and enzyme replacement therapies, both of which are limited in their effects. In this work, knockout (KO) MPS I mice were treated with a nonviral vector containing the human IDUA cDNA. KO mice were transfected by hydrodynamic injection of pRIDUA in the caudal vein (i.v., n = 3) or by intraperitoneal injection of pRIDUA/Superfect complexes (i.p., n = 3). GAG concentration and IDUA activity were analysed in the kidneys, spleen, lungs, brain and liver. The expression of IDUA in the organs of i.v.- and i.p.-treated mice was also analysed by real-time reverse-transcription (RT) PCR and compared by relative quantification. The concentration of GAGs in the organs differed between KO and wild-type mice. In the spleen and liver, GAG levels were lower in i.v.- and i.p.-treated KO mice than in control nontreated animals. Real-time RT-PCR showed that the transgene is expressed in all the analysed organs of i.p.- and i.v.-treated KO mice. Enzyme activity was similarly observed in all the organs analysed. Our data suggest that this kind of transfection may be a useful tool for studies of nonviral protocols for gene therapy of MPS.
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References
Aliño SF, Crespo A, Dasi F (2003) Long-term therapeutic levels of human alpha-1 antitrypsin in plasma after hydrodynamic injection of nonviral DNA. Gene Ther 10: 1672–1679.
Anson DS, Bielicki J, Hopwood JJ (1992) Correction of mucopolysaccharidosis type I fibroblasts by retroviral-mediated transfer of the human alpha-L-iduronidase gene. Hum Gene Ther 3: 371–379.
Baxter MA, Wynn RF, Deakin JA, et al (2002) Retrovirally mediated correction of bone marrow-derived mesenchymal stem cells from patients with mucopolysaccharidosis type I. Blood 99: 1857–1859.
Clements PR, Muller V, Hopwood JJ (1985) Human alpha-L-iduronidase. 2. Catalytic properties. Eur J Biochem 152: 29–34.
Crespo A, Peydró A, Dasí F, et al (2005) Hydrodynamic liver gene transfer mechanism involves transient sinusoidal blood stasis and massive hepatocyte endocytic vesicles. Gene Ther 12: 927–935.
de Jong JGN, Wevers RA, Liebrand-van Sambeek R (1992) Measuring urinary glycosaminoglycans in the presence of protein: an improved screening procedure for mucopolysaccharidoses based on dimethylmethylene blue. Clin Chem 38: 803–807.
Desmaris N, Verot L, Puech JP, Caillaud C, Vanier MT, Heard JM (2004) Prevention of neuropathology in the mouse model of Hurler syndrome. Ann Neurol 56: 68–76.
Domenico CD, Villani GRD, Napoli DD, et al (2005) Gene therapy for a mucopolysaccharidosis type I murine model with lentiviral-IDUA vector. Hum Gene Ther 16: 81–90.
Fairbairn LJ, Lashford LS, Spooncer E, et al (1996) Long-term in vitro correction of α-L-iduronidase deficiency (Hurler syndrome) in human bone marrow. Proc Natl Acad Sci USA 93: 2025–2030.
Hartung SD, Frandsen JL, Pan D, et al (2004) Correction of metabolic, craniofacial, and neurologic abnormalities in MPS I mice treated at birth with adeno-associated virus vector transducing the human alpha-L-iduronidase gene. Mol Ther 9: 866–875.
He CX, Shi D, Wu WJ, et al (2004) Insulin expression in livers of diabetic mice mediated by hydrodynamics-based administration. World J Gastroenterol 10: 567–572.
Herweijer H, Wolff JA (2003) Progress and prospects: naked DNA gene transfer and therapy. Gene Ther 10: 453–458.
Huang MM, Wong A, Yu X, Kakkis E, Kohn DB (1997) Retrovirus-mediated transfer of the human alpha-L-iduronidase cDNA into human hematopoietic progenitor cells leads to correction in trans of Hurler fibroblasts. Gene Ther 4: 1150–1159.
Kakkis ED, Muenzer J, Tiller GE, et al (2001) Enzyme-replacement therapy in mucopolysaccharidosis I. N Engl J Med 344: 182–188.
Kobayashi H, Carbonaro D, Pepper K, et al (2005) Neonatal gene therapy of MPSI mice by intravenous injection of a lentiviral vector. Mol Ther 11: 776–789.
Liu F, Song YK, Liu D (1999) Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA. Gene Ther 6: 1258–1266.
Liu Y, Xu L, Hennig AK, et al (2005) Liver-directed neonatal gene therapy prevents cardiac, bone, ear, and eye disease in mucopolysaccharidosis I mice. Mol Ther 11: 35–47.
McKusick VA (1972) Heritable Disorders of Connective Tissue, 4th edn. St. Louis, MO: C. V. Mosby.
Marechal V, Dehee A, Chikhi-Brachet R, Piolot T, Coppey-Moisan M, Nicolas JC (1999) Mapping EBNA-1 domains involved in binding to metaphase chromosomes. J Virol 73: 4385–4392.
Matte U, Yogalingam G, Brooks D, et al (2003) Identification and characterization of 13 new mutations in mucopolysaccharidosis type I patients. Mol Genet Metab 78: 37–43.
Ohmi K, Greenberg DS, Rajavel KS, Ryazantsev S, Li HH, Neufeld EF (2003) Activated microglia in cortex of mouse models of mucopolysaccharidoses I and IIIB. Proc Natl Acad Sci USA 100: 1902–1907.
Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29: 2003–2007.
Pfaffl MW, Horgan GW, Dempfle L (2002) Relative expression software tool (REST-384©) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 30: 1–10.
Sambrook J., Fritsch EF, Maniatis T (1989) Molecular Cloning: A Laboratory Manual, 2nd edn. Cold Spring Harbor: Cold Spring Harbor Laboratory Press.
Santos DG, Nardi NB, Chies JAB, Braga LM, Camassola M, Kvitko K (2003) Caracterização de camundongos nocaute para protocolo pré-clínico de terapia gênica de MPS I. XV Salão de Iniciação Científica, Porto Alegre, RS, Brasil, 520.
Song YK, Liu F, Zhang G, Liu D (2002) Hydrodynamics-based transfection: simple and efficient method for introducing and expressing transgenes in animals by intravenous injection of DNA. Methods Enzymol 346: 92–105.
Stein CS, Kang Y, Sauter SL, et al (2001) In vivo treatment of hemophilia A and mucopolysaccharidosis type VII using nonprimate lentiviral vectors. Mol Ther 3: 850–856.
Teixeira LA, Fricke CH, Bonorino CB, Bogo MR, Nardi NB (2001) An efficient gene transfer system for hematopoietic cell line using transient and stable vectors. J Biotechnol 88: 159–165.
Thierry AR, Iskandar YL, Bryant JL, et al (1995) Systemic gene therapy: biodistribution and long-term expression of a transgene in mice. Proc Natl Acad Sci USA 92: 9742–9746.
Vellodi A, Young EP, Cooper A, et al (1997) Bone marrow transplantation for mucopolysaccharidosis type I: experience of two British centres. Arch Dis Child 76: 92–99.
Whitley CB, Belani KG, Chang PN, et al (1993) Long-term outcome of Hurler syndrome following bone marrow transplantation. Am J Med Genet 46: 209–218.
Zheng Y, Rozengurt N, Ryazantsev S, Kohn DB, Satake N, Neufeld EF (2003) Treatment of the mouse model of mucopolysaccharidosis I with retrovirally transduced bone marrow. Mol Genet Metab 79: 233–244.
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Camassola, M., Braga, L.M., Delgado-Cañedo, A. et al. Nonviral in vivo gene transfer in the mucopolysaccharidosis I murine model. J Inherit Metab Dis 28, 1035–1043 (2005). https://doi.org/10.1007/s10545-005-0070-5
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DOI: https://doi.org/10.1007/s10545-005-0070-5