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Gene Therapy for the Treatment of Neurological Disorders: Metabolic Disorders

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Gene Therapy for Neurological Disorders

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1382))

Abstract

Metabolic disorders comprise a large group of heterogeneous diseases ranging from very prevalent diseases such as diabetes mellitus to rare genetic disorders like Canavan Disease. Whether either of these diseases is amendable by gene therapy depends to a large degree on the knowledge of their pathomechanism, availability of the therapeutic gene, vector selection, and availability of suitable animal models. In this book chapter, we review three metabolic disorders of the central nervous system (CNS; Canavan Disease, Niemann–Pick disease and Phenylketonuria) to give examples for primary and secondary metabolic disorders of the brain and the attempts that have been made to use adeno-associated virus (AAV) based gene therapy for treatment. Finally, we highlight commonalities and obstacles in the development of gene therapy for metabolic disorders of the CNS exemplified by those three diseases.

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References

  1. Wang D, Zhong L, Nahid MA, Gao G (2014) The potential of adeno-associated viral vectors for gene delivery to muscle tissue. Expert Opin Drug Deliv 11:345–364

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Rebuffat A, Harding CO, Ding Z, Thony B (2010) Comparison of adeno-associated virus pseudotype 1, 2, and 8 vectors administered by intramuscular injection in the treatment of murine phenylketonuria. Hum Gene Ther 21:463–477

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Mueller C et al (2012) Sustained miRNA-mediated knockdown of mutant AAT with simultaneous augmentation of wild-type AAT has minimal effect on global liver miRNA profiles. Mol Ther 20:590–600

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. McGovern MM et al (2008) A prospective, cross-sectional survey study of the natural history of Niemann-Pick disease type B. Pediatrics 122:e341–e349

    Article  PubMed Central  PubMed  Google Scholar 

  5. Vanier MT (2010) Niemann-Pick disease type C. Orphanet J Rare Dis 5:16

    Article  PubMed Central  PubMed  Google Scholar 

  6. Brady RO, Kanfer JN, Mock MB, Fredrickson DS (1966) The metabolism of sphingomyelin. II. Evidence of an enzymatic deficiency in Niemann-Pick disease. Proc Natl Acad Sci U S A 55:366–369

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Kolodny EH (2000) Niemann-Pick disease. Curr Opin Hematol 7:48–52

    Article  CAS  PubMed  Google Scholar 

  8. McGovern MM, Aron A, Brodie SE, Desnick RJ, Wasserstein MP (2006) Natural history of Type A Niemann-Pick disease: possible endpoints for therapeutic trials. Neurology 66:228–232

    Article  CAS  PubMed  Google Scholar 

  9. Walterfang M et al (2012) Dysphagia as a risk factor for mortality in Niemann-Pick disease type C: systematic literature review and evidence from studies with miglustat. Orphanet J Rare Dis 7:76

    Article  PubMed Central  PubMed  Google Scholar 

  10. NP-C Guidelines Working Group et al (2009) Recommendations on the diagnosis and management of Niemann-Pick disease type C. Mol Genet Metab 98:152–165

    Article  CAS  Google Scholar 

  11. Schuchman EH (2007) The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease. J Inherit Metab Dis 30:654–663

    Article  CAS  PubMed  Google Scholar 

  12. Meikle PJ, Hopwood JJ, Clague AE, Carey WF (1999) Prevalence of lysosomal storage disorders. JAMA 281:249–254

    Article  CAS  PubMed  Google Scholar 

  13. Landrieu P, Said G (1984) Peripheral neuropathy in type A Niemann-Pick disease. A morphological study. Acta Neuropathol 63:66–71

    Article  CAS  PubMed  Google Scholar 

  14. McGovern MM et al (2004) Lipid abnormalities in children with types A and B Niemann Pick disease. J Pediatr 145:77–81

    Article  CAS  PubMed  Google Scholar 

  15. Wasserstein MP et al (2003) Growth restriction in children with type B Niemann-Pick disease. J Pediatr 142:424–428

    Article  PubMed  Google Scholar 

  16. McGovern MM et al (2004) Ocular manifestations of Niemann-Pick disease type B. Ophthalmology 111:1424–1427

    Article  PubMed  Google Scholar 

  17. Spiegel R et al (2009) The clinical spectrum of fetal Niemann-Pick type C. Am J Med Genet A 149A:446–450

    Article  CAS  PubMed  Google Scholar 

  18. Fink JK et al (1989) Clinical spectrum of Niemann-Pick disease type C. Neurology 39:1040–1049

    Article  CAS  PubMed  Google Scholar 

  19. Graber D, Salvayre R, Levade T (1994) Accurate differentiation of neuronopathic and nonneuronopathic forms of Niemann-Pick disease by evaluation of the effective residual lysosomal sphingomyelinase activity in intact cells. J Neurochem 63:1060–1068

    Article  CAS  PubMed  Google Scholar 

  20. Vanier MT et al (1985) Biochemical studies in Niemann-Pick disease. III. In vitro and in vivo assays of sphingomyelin degradation in cultured skin fibroblasts and amniotic fluid cells for the diagnosis of the various forms of the disease. Clin Genet 27:20–32

    Article  CAS  PubMed  Google Scholar 

  21. Carstea ED et al (1997) Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science 277:228–231

    Article  CAS  PubMed  Google Scholar 

  22. Vanier MT, Millat G (2003) Niemann-Pick disease type C. Clin Genet 64:269–281

    Article  CAS  PubMed  Google Scholar 

  23. Dhami R, Schuchman EH (2004) Mannose 6-phosphate receptor-mediated uptake is defective in acid sphingomyelinase-deficient macrophages: implications for Niemann-Pick disease enzyme replacement therapy. J Biol Chem 279:1526–1532

    Article  CAS  PubMed  Google Scholar 

  24. Kornfeld S (1987) Trafficking of lysosomal enzymes. FASEB J 1:462–468

    CAS  PubMed  Google Scholar 

  25. Sands MS, Davidson BL (2006) Gene therapy for lysosomal storage diseases. Mol Ther 13:839–849

    Article  CAS  PubMed  Google Scholar 

  26. Mencarelli C, Martinez-Martinez P (2013) Ceramide function in the brain: when a slight tilt is enough. Cell Mol Life Sci 70:181–203

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Jiang W, Ogretmen B (2014) Autophagy paradox and ceramide. Biochim Biophys Acta 1841(5):783–792

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Rego A et al (2012) Modulation of mitochondrial outer membrane permeabilization and apoptosis by ceramide metabolism. PLoS One 7:e48571

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Schuchman EH (2010) Acid sphingomyelinase, cell membranes and human disease: lessons from Niemann-Pick disease. FEBS Lett 584:1895–1900

    Article  CAS  PubMed  Google Scholar 

  30. Smith EL, Schuchman EH (2008) The unexpected role of acid sphingomyelinase in cell death and the pathophysiology of common diseases. FASEB J 22:3419–3431

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Miyawaki S, Mitsuoka S, Sakiyama T, Kitagawa T (1982) Sphingomyelinosis, a new mutation in the mouse: a model of Niemann-Pick disease in humans. J Hered 73:257–263

    CAS  PubMed  Google Scholar 

  32. Pentchev PG et al (1980) A lysosomal storage disorder in mice characterized by a dual deficiency of sphingomyelinase and glucocerebrosidase. Biochim Biophys Acta 619:669–679

    Article  CAS  PubMed  Google Scholar 

  33. Pentchev PG et al (1984) A genetic storage disorder in BALB/C mice with a metabolic block in esterification of exogenous cholesterol. J Biol Chem 259:5784–5791

    CAS  PubMed  Google Scholar 

  34. Nakashima S et al (1984) A mouse model for Niemann-Pick disease: phospholipid class and fatty acid composition of various tissues. J Lipid Res 25:219–227

    CAS  PubMed  Google Scholar 

  35. Horinouchi K, Sakiyama T, Pereira L, Lalley PA, Schuchman EH (1993) Mouse models of Niemann-Pick disease: mutation analysis and chromosomal mapping rule out the type A and B forms. Genomics 18:450–451

    Article  CAS  PubMed  Google Scholar 

  36. Horinouchi K et al (1995) Acid sphingomyelinase deficient mice: a model of types A and B Niemann-Pick disease. Nat Genet 10:288–293

    Article  CAS  PubMed  Google Scholar 

  37. Otterbach B, Stoffel W (1995) Acid sphingomyelinase-deficient mice mimic the neurovisceral form of human lysosomal storage disease (Niemann-Pick disease). Cell 81:1053–1061

    Article  CAS  PubMed  Google Scholar 

  38. Marathe S et al (2000) Creation of a mouse model for non-neurological (type B) Niemann-Pick disease by stable, low level expression of lysosomal sphingomyelinase in the absence of secretory sphingomyelinase: relationship between brain intra-lysosomal enzyme activity and central nervous system function. Hum Mol Genet 9:1967–1976

    Article  CAS  PubMed  Google Scholar 

  39. Maue RA et al (2012) A novel mouse model of Niemann-Pick type C disease carrying a D1005G-Npc1 mutation comparable to commonly observed human mutations. Hum Mol Genet 21:730–750

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Loftus SK et al (1997) Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene. Science 277:232–235

    Article  CAS  PubMed  Google Scholar 

  41. Gartner JC Jr et al (1986) Progression of neurovisceral storage disease with supranuclear ophthalmoplegia following orthotopic liver transplantation. Pediatrics 77:104–106

    PubMed Central  PubMed  Google Scholar 

  42. Daloze P et al (1977) Replacement therapy for inherited enzyme deficiency: liver orthotopic transplantation in Niemann-Pick disease type A. Am J Med Genet 1:229–239

    Article  CAS  PubMed  Google Scholar 

  43. Scaggiante B et al (1987) Successful therapy of Niemann-Pick disease by implantation of human amniotic membrane. Transplantation 44:59–61

    Article  CAS  PubMed  Google Scholar 

  44. Victor S et al (2003) Niemann-Pick disease: sixteen-year follow-up of allogeneic bone marrow transplantation in a type B variant. J Inherit Metab Dis 26:775–785

    Article  CAS  PubMed  Google Scholar 

  45. Bayever E et al (1992) Bone marrow transplantation for Niemann-Pick type IA disease. J Inherit Metab Dis 15:919–928

    Article  CAS  PubMed  Google Scholar 

  46. Vellodi A, Hobbs JR, O’Donnell NM, Coulter BS, Hugh-Jones K (1987) Treatment of Niemann-Pick disease type B by allogeneic bone marrow transplantation. Br Med J (Clin Res Ed) 295:1375–1376

    Article  CAS  Google Scholar 

  47. Miranda SR et al (2000) Infusion of recombinant human acid sphingomyelinase into Niemann-Pick disease mice leads to visceral, but not neurological, correction of the pathophysiology. FASEB J 14:1988–1995

    Article  CAS  PubMed  Google Scholar 

  48. Suchi M et al (1992) Retroviral-mediated transfer of the human acid sphingomyelinase cDNA: correction of the metabolic defect in cultured Niemann-Pick disease cells. Proc Natl Acad Sci U S A 89:3227–3231

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Miranda SR, Erlich S, Friedrich VL Jr, Gatt S, Schuchman EH (2000) Hematopoietic stem cell gene therapy leads to marked visceral organ improvements and a delayed onset of neurological abnormalities in the acid sphingomyelinase deficient mouse model of Niemann-Pick disease. Gene Ther 7:1768–1776

    Article  CAS  PubMed  Google Scholar 

  50. Jin HK, Carter JE, Huntley GW, Schuchman EH (2002) Intracerebral transplantation of mesenchymal stem cells into acid sphingomyelinase-deficient mice delays the onset of neurological abnormalities and extends their life span. J Clin Invest 109:1183–1191

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Jin HK, Schuchman EH (2003) Ex vivo gene therapy using bone marrow-derived cells: combined effects of intracerebral and intravenous transplantation in a mouse model of Niemann-Pick disease. Mol Ther 8:876–885

    Article  CAS  PubMed  Google Scholar 

  52. Barbon CM et al (2005) AAV8-mediated hepatic expression of acid sphingomyelinase corrects the metabolic defect in the visceral organs of a mouse model of Niemann-Pick disease. Mol Ther 12:431–440

    Article  CAS  PubMed  Google Scholar 

  53. Passini MA et al (2005) AAV vector-mediated correction of brain pathology in a mouse model of Niemann-Pick A disease. Mol Ther 11:754–762

    Article  CAS  PubMed  Google Scholar 

  54. Dodge JC et al (2005) Gene transfer of human acid sphingomyelinase corrects neuropathology and motor deficits in a mouse model of Niemann-Pick type A disease. Proc Natl Acad Sci U S A 102:17822–17827

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Passini MA et al (2007) Combination brain and systemic injections of AAV provide maximal functional and survival benefits in the Niemann-Pick mouse. Proc Natl Acad Sci U S A 104:9505–9510

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Salegio EA et al (2010) Magnetic resonance imaging-guided delivery of adeno-associated virus type 2 to the primate brain for the treatment of lysosomal storage disorders. Hum Gene Ther 21:1093–1103

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Bu J et al (2012) Merits of combination cortical, subcortical, and cerebellar injections for the treatment of Niemann-Pick disease type A. Mol Ther 20:1893–1901

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Salegio EA et al (2012) Safety study of adeno-associated virus serotype 2-mediated human acid sphingomyelinase expression in the nonhuman primate brain. Hum Gene Ther 23:891–902

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Woo SL, Lidsky AS, Guttler F, Chandra T, Robson KJ (1983) Cloned human phenylalanine hydroxylase gene allows prenatal diagnosis and carrier detection of classical phenylketonuria. Nature 306:151–155

    Article  CAS  PubMed  Google Scholar 

  60. Folling I (1994) The discovery of phenylketonuria. Acta Paediatr 407:4–10

    Article  CAS  Google Scholar 

  61. National Institutes of Health Consensus Development Panel (2001) National Institutes of Health Consensus Development Conference Statement: phenylketonuria: screening and management, October 16–18, 2000. Pediatrics 108:972–982

    Article  Google Scholar 

  62. Loeber JG (2007) Neonatal screening in Europe; the situation in 2004. J Inherit Metab Dis 30:430–438

    Article  PubMed  Google Scholar 

  63. Ozalp I et al (2001) Newborn PKU screening in Turkey: at present and organization for future. Turk J Pediatr 43:97–101

    CAS  PubMed  Google Scholar 

  64. White DA, Waisbren S, van Spronsen FJ (2010) The psychology and neuropathology of phenylketonuria. Mol Genet Metab 99(Suppl 1):S1–S2

    Article  CAS  PubMed  Google Scholar 

  65. Pietz J, Benninger C, Schmidt H, Scheffner D, Bickel H (1988) Long-term development of intelligence (IQ) and EEG in 34 children with phenylketonuria treated early. Eur J Pediatr 147:361–367

    Article  CAS  PubMed  Google Scholar 

  66. Lichter-Konecki U, Hipke CM, Konecki DS (1999) Human phenylalanine hydroxylase gene expression in kidney and other nonhepatic tissues. Mol Genet Metab 67:308–316

    Article  CAS  PubMed  Google Scholar 

  67. Barranger JA, Geiger PJ, Huzino A, Bessman SP (1972) Isozymes of phenylalanine hydroxylase. Science 175:903–905

    Article  CAS  PubMed  Google Scholar 

  68. Robson KJ, Chandra T, MacGillivray RT, Woo SL (1982) Polysome immunoprecipitation of phenylalanine hydroxylase mRNA from rat liver and cloning of its cDNA. Proc Natl Acad Sci U S A 79:4701–4705

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Udenfriend S, Cooper JR (1952) The enzymatic conversion of phenylalanine to tyrosine. J Biol Chem 194:503–511

    CAS  PubMed  Google Scholar 

  70. Li J, Dangott LJ, Fitzpatrick PF (2010) Regulation of phenylalanine hydroxylase: conformational changes upon phenylalanine binding detected by hydrogen/deuterium exchange and mass spectrometry. Biochemistry 49:3327–3335

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Surtees R, Blau N (2000) The neurochemistry of phenylketonuria. Eur J Pediatr 159(Suppl 2):S109–S113

    Article  CAS  PubMed  Google Scholar 

  72. Friedman PA, Kaufman S, Kang ES (1972) Nature of the molecular defect in phenylketonuria and hyperphenylalaninaemia. Nature 240:157–159

    Article  CAS  PubMed  Google Scholar 

  73. Justice P, O’Flynn ME, Hsia DY (1967) Phenylalanine-hydroxylase activity in hyperphenylalaninaemia. Lancet 1:928–929

    Article  CAS  PubMed  Google Scholar 

  74. Binek-Singer P, Johnson TC (1982) The effects of chronic hyperphenylalaninaemia on mouse brain protein synthesis can be prevented by other amino acids. Biochem J 206:407–414

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Pietz J et al (1999) Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. J Clin Invest 103:1169–1178

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. Matalon R et al (2003) Future role of large neutral amino acids in transport of phenylalanine into the brain. Pediatrics 112:1570–1574

    PubMed  Google Scholar 

  77. Schindeler S et al (2007) The effects of large neutral amino acid supplements in PKU: an MRS and neuropsychological study. Mol Genet Metab 91:48–54

    Article  CAS  PubMed  Google Scholar 

  78. Hughes JV, Johnson TC (1978) Experimentally induced and natural recovery from the effects of phenylalanine on brain protein synthesis. Biochim Biophys Acta 517:473–485

    Article  CAS  PubMed  Google Scholar 

  79. Binek PA, Johnson TC, Kelly CJ (1981) Effect of alpha-methylphenylalanine and phenylalanine on brain polyribosomes and protein synthesis. J Neurochem 36:1476–1484

    Article  CAS  PubMed  Google Scholar 

  80. Pascucci T et al (2009) 5-Hydroxytryptophan rescues serotonin response to stress in prefrontal cortex of hyperphenylalaninaemic mice. Int J Neuropsychopharmacol 12:1067–1079

    Article  CAS  PubMed  Google Scholar 

  81. Puglisi-Allegra S et al (2000) Dramatic brain aminergic deficit in a genetic mouse model of phenylketonuria. Neuroreport 11:1361–1364

    Article  CAS  PubMed  Google Scholar 

  82. Burlina AB et al (2000) Measurement of neurotransmitter metabolites in the cerebrospinal fluid of phenylketonuric patients under dietary treatment. J Inherit Metab Dis 23:313–316

    Article  CAS  PubMed  Google Scholar 

  83. Pascucci T, Ventura R, Puglisi-Allegra S, Cabib S (2002) Deficits in brain serotonin synthesis in a genetic mouse model of phenylketonuria. Neuroreport 13:2561–2564

    Article  CAS  PubMed  Google Scholar 

  84. McKean CM (1972) The effects of high phenylalanine concentrations on serotonin and catecholamine metabolism in the human brain. Brain Res 47:469–476

    Article  CAS  PubMed  Google Scholar 

  85. Curtius HC et al (1981) Serotonin and dopamine synthesis in phenylketonuria. Adv Exp Med Biol 133:277–291

    Article  CAS  PubMed  Google Scholar 

  86. Lou HC, Guttler F, Lykkelund C, Bruhn P, Niederwieser A (1985) Decreased vigilance and neurotransmitter synthesis after discontinuation of dietary treatment for phenylketonuria in adolescents. Eur J Pediatr 144:17–20

    Article  CAS  PubMed  Google Scholar 

  87. Kienzle Hagen ME et al (2002) Experimental hyperphenylalaninemia provokes oxidative stress in rat brain. Biochim Biophys Acta 1586:344–352

    Article  CAS  PubMed  Google Scholar 

  88. Lu L et al (2011) Mechanisms regulating superoxide generation in experimental models of phenylketonuria: an essential role of NADPH oxidase. Mol Genet Metab 104:241–248

    Article  CAS  PubMed  Google Scholar 

  89. Poncet IB, Berry HK, Butcher RE, Kazmaier KJ (1975) Biochemical effects of induced phenylketonuria in rats. Biol Neonate 26:88–101

    Article  CAS  PubMed  Google Scholar 

  90. Dhondt JL, Dautrevaux M, Biserte G, Farriaux JP (1977) A new experimental model of hyperphenylalaninemia in rat. Effect of p-chlorophenylalanine and cotrimoxazole. Biochimie 59:713–717

    Article  CAS  PubMed  Google Scholar 

  91. Schalock RL, Brown WJ, Copenhaver JH, Gunter R (1975) Model phenylketonuria (PKU) in the albino rat: behaviroal, biochemical, and neuroanatomical effects. J Comp Physiol Psychol 89:655–666

    Article  CAS  PubMed  Google Scholar 

  92. McDonald JD et al (1988) Biochemical defect of the hph-1 mouse mutant is a deficiency in GTP-cyclohydrolase activity. J Neurochem 50:655–657

    Article  CAS  PubMed  Google Scholar 

  93. Bode VC, McDonald JD, Guenet JL, Simon D (1988) hph-1: a mouse mutant with hereditary hyperphenylalaninemia induced by ethylnitrosourea mutagenesis. Genetics 118:299–305

    PubMed Central  CAS  PubMed  Google Scholar 

  94. McDonald JD, Bode VC, Dove WF, Shedlovsky A (1990) The use of N-ethyl-N-nitrosourea to produce mouse models for human phenylketonuria and hyperphenylalaninemia. Prog Clin Biol Res 340C:407–413

    CAS  PubMed  Google Scholar 

  95. McDonald JD, Bode VC, Dove WF, Shedlovsky A (1990) Pahhph-5: a mouse mutant deficient in phenylalanine hydroxylase. Proc Natl Acad Sci U S A 87:1965–1967

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  96. Shedlovsky A, McDonald JD, Symula D, Dove WF (1993) Mouse models of human phenylketonuria. Genetics 134:1205–1210

    PubMed Central  CAS  PubMed  Google Scholar 

  97. McDonald JD, Charlton CK (1997) Characterization of mutations at the mouse phenylalanine hydroxylase locus. Genomics 39:402–405

    Article  CAS  PubMed  Google Scholar 

  98. Ding Z et al (2008) Correction of murine PKU following AAV-mediated intramuscular expression of a complete phenylalanine hydroxylating system. Mol Ther 16:673–681

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  99. Harding CO et al (2006) Complete correction of hyperphenylalaninemia following liver-directed, recombinant AAV2/8 vector-mediated gene therapy in murine phenylketonuria. Gene Ther 13:457–462

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  100. Ding Z, Georgiev P, Thony B (2006) Administration-route and gender-independent long-term therapeutic correction of phenylketonuria (PKU) in a mouse model by recombinant adeno-associated virus 8 pseudotyped vector-mediated gene transfer. Gene Ther 13:587–593

    Article  CAS  PubMed  Google Scholar 

  101. Oh HJ, Park ES, Kang S, Jo I, Jung SC (2004) Long-term enzymatic and phenotypic correction in the phenylketonuria mouse model by adeno-associated virus vector-mediated gene transfer. Pediatr Res 56:278–284

    Article  CAS  PubMed  Google Scholar 

  102. Mochizuki S et al (2004) Long-term correction of hyperphenylalaninemia by AAV-mediated gene transfer leads to behavioral recovery in phenylketonuria mice. Gene Ther 11:1081–1086

    Article  CAS  PubMed  Google Scholar 

  103. Fang B et al (1994) Gene therapy for phenylketonuria: phenotypic correction in a genetically deficient mouse model by adenovirus-mediated hepatic gene transfer. Gene Ther 1:247–254

    CAS  PubMed  Google Scholar 

  104. Harding CO, Neff M, Jones K, Wild K, Wolff JA (2003) Expression of phenylalanine hydroxylase (PAH) in erythrogenic bone marrow does not correct hyperphenylalaninemia in Pah(enu2) mice. J Gene Med 5:984–993

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  105. Nagasaki Y et al (1999) Reversal of hypopigmentation in phenylketonuria mice by adenovirus-mediated gene transfer. Pediatr Res 45:465–473

    Article  CAS  PubMed  Google Scholar 

  106. Lin CM, Tan Y, Lee YM, Chang CC, Hsiao KJ (1997) Expression of human phenylalanine hydroxylase activity in T lymphocytes of classical phenylketonuria children by retroviral-mediated gene transfer. J Inherit Metab Dis 20:742–754

    Article  CAS  PubMed  Google Scholar 

  107. Ledley FD, Grenett HE, DiLella AG, Kwok SC, Woo SL (1985) Gene transfer and expression of human phenylalanine hydroxylase. Science 228:77–79

    Article  CAS  PubMed  Google Scholar 

  108. Robson KJ et al (1984) Sequence comparison of rat liver phenylalanine hydroxylase and its cDNA clones. Biochemistry 23:5671–5675

    Article  CAS  PubMed  Google Scholar 

  109. Kwok SC, Ledley FD, DiLella AG, Robson KJ, Woo SL (1985) Nucleotide sequence of a full-length complementary DNA clone and amino acid sequence of human phenylalanine hydroxylase. Biochemistry 24:556–561

    Article  CAS  PubMed  Google Scholar 

  110. Ledley FD, Grenett HE, McGinnis-Shelnutt M, Woo SL (1986) Retroviral-mediated gene transfer of human phenylalanine hydroxylase into NIH 3T3 and hepatoma cells. Proc Natl Acad Sci U S A 83:409–413

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  111. Ding Z, Harding CO, Thony B (2004) State-of-the-art 2003 on PKU gene therapy. Mol Genet Metab 81:3–8

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  112. Oh HJ et al (2005) Reversal of gene expression profile in the phenylketonuria mouse model after adeno-associated virus vector-mediated gene therapy. Mol Genet Metab 86(Suppl 1):S124–S132

    Article  CAS  PubMed  Google Scholar 

  113. Embury JE et al (2007) PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pah(enu2) mice. Brain Res 1127:136–150

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  114. Yagi H et al (2011) Complete restoration of phenylalanine oxidation in phenylketonuria mouse by a self-complementary adeno-associated virus vector. J Gene Med 13:114–122

    Article  CAS  PubMed  Google Scholar 

  115. Duncan AW, Dorrell C, Grompe M (2009) Stem cells and liver regeneration. Gastroenterology 137:466–481

    Article  PubMed Central  PubMed  Google Scholar 

  116. van Bogaert L, Bertrand I (1949) Sur une idiotie familiale avec degerescence sponglieuse de neuraxe (note preliminaire). Acta Neurol Belg 49:572–587

    Google Scholar 

  117. Matalon R et al (1988) Aspartoacylase deficiency and N-acetylaspartic aciduria in patients with Canavan disease. Am J Med Genet 29:463–471

    Article  CAS  PubMed  Google Scholar 

  118. Matalon R, Michals K, Kaul R (1995) Canavan disease: from spongy degeneration to molecular analysis. J Pediatr 127:511–517

    Article  CAS  PubMed  Google Scholar 

  119. Adachi M, Schneck L, Cara J, Volk BW (1973) Spongy degeneration of the central nervous system (van Bogaert and Bertrand type; Canavan’s disease). A review. Hum Pathol 4:331–347

    Article  CAS  PubMed  Google Scholar 

  120. Traeger EC, Rapin I (1998) The clinical course of Canavan disease. Pediatr Neurol 18:207–212

    Article  CAS  PubMed  Google Scholar 

  121. Matalon R, Michals-Matalon K (1998) Molecular basis of Canavan disease. Eur J Paediatr Neurol 2:69–76

    Article  CAS  PubMed  Google Scholar 

  122. Sreenivasan P, Purushothaman KK (2013) Radiological clue to diagnosis of Canavan disease. Indian J Pediatr 80(1):75–77

    Article  PubMed  Google Scholar 

  123. Pradhan S, Goyal G (2011) Teaching NeuroImages: honeycomb appearance of the brain in a patient with Canavan disease. Neurology 76:e68

    Article  PubMed  Google Scholar 

  124. Francis JS, Markov V, Leone P (2014) Dietary triheptanoin rescues oligodendrocyte loss, dysmyelination and motor function in the nur7 mouse model of Canavan disease. J Inherit Metab Dis 37(3):369–381

    Article  CAS  PubMed  Google Scholar 

  125. Ariyannur PS, Madhavarao CN, Namboodiri AM (2008) N-acetylaspartate synthesis in the brain: mitochondria vs. microsomes. Brain Res 1227:34–41

    Article  CAS  PubMed  Google Scholar 

  126. Urenjak J, Williams SR, Gadian DG, Noble M (1992) Specific expression of N-acetylaspartate in neurons, oligodendrocyte-type-2 astrocyte progenitors, and immature oligodendrocytes in vitro. J Neurochem 59:55–61

    Article  CAS  PubMed  Google Scholar 

  127. Moffett JR, Namboodiri MA, Cangro CB, Neale JH (1991) Immunohistochemical localization of N-acetylaspartate in rat brain. Neuroreport 2:131–134

    Article  CAS  PubMed  Google Scholar 

  128. Mersmann N et al (2011) Aspartoacylase-lacZ knockin mice: an engineered model of Canavan disease. PLoS One 6:e20336

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  129. Kirmani BF, Jacobowitz DM, Kallarakal AT, Namboodiri MA (2002) Aspartoacylase is restricted primarily to myelin synthesizing cells in the CNS: therapeutic implications for Canavan disease. Brain Res Mol Brain Res 107:176–182

    Article  CAS  PubMed  Google Scholar 

  130. Baslow MH (1999) The existence of molecular water pumps in the nervous system: a review of the evidence. Neurochem Int 34:77–90

    Article  CAS  PubMed  Google Scholar 

  131. Baslow MH (1999) Molecular water pumps and the aetiology of Canavan disease: a case of the sorcerer’s apprentice. J Inherit Metab Dis 22:99–101

    Article  CAS  PubMed  Google Scholar 

  132. Moffett JR, Ross B, Arun P, Madhavarao CN, Namboodiri AM (2007) N-Acetylaspartate in the CNS: from neurodiagnostics to neurobiology. Prog Neurobiol 81:89–131

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  133. Taylor DL et al (1995) Investigation into the role of N-acetylaspartate in cerebral osmoregulation. J Neurochem 65:275–281

    Article  CAS  PubMed  Google Scholar 

  134. Davies SE, Gotoh M, Richards DA, Obrenovitch TP (1998) Hypoosmolarity induces an increase of extracellular N-acetylaspartate concentration in the rat striatum. Neurochem Res 23:1021–1025

    Article  CAS  PubMed  Google Scholar 

  135. Namboodiri AM et al (2006) Canavan disease and the role of N-acetylaspartate in myelin synthesis. Mol Cell Endocrinol 252:216–223

    Article  CAS  PubMed  Google Scholar 

  136. Kirmani BF, Jacobowitz DM, Namboodiri MA (2003) Developmental increase of aspartoacylase in oligodendrocytes parallels CNS myelination. Brain Res Dev Brain Res 140:105–115

    Article  CAS  PubMed  Google Scholar 

  137. D’Adamo AF Jr, Gidez LI, Yatsu FM (1968) Acetyl transport mechanisms. Involvement of N-acetyl aspartic acid in de novo fatty acid biosynthesis in the developing rat brain. Exp Brain Res 5:267–273

    PubMed  Google Scholar 

  138. Pliss L et al (2003) Morphology and ultrastructure of rat hippocampal formation after i.c.v. administration of N-acetyl-L-aspartyl-L-glutamate. Neuroscience 122:93–101

    Article  CAS  PubMed  Google Scholar 

  139. Kitada K et al (2000) Accumulation of N-acetyl-L-aspartate in the brain of the tremor rat, a mutant exhibiting absence-like seizure and spongiform degeneration in the central nervous system. J Neurochem 74:2512–2519

    Article  CAS  PubMed  Google Scholar 

  140. Akimitsu T et al (2000) Epileptic seizures induced by N-acetyl-L-aspartate in rats: in vivo and in vitro studies. Brain Res 861:143–150

    Article  CAS  PubMed  Google Scholar 

  141. Kolodziejczyk K, Hamilton NB, Wade A, Karadottir R, Attwell D (2009) The effect of N-acetyl-aspartyl-glutamate and N-acetyl-aspartate on white matter oligodendrocytes. Brain 132:1496–1508

    Article  PubMed Central  PubMed  Google Scholar 

  142. Surendran S (2010) Upregulation of N-acetylaspartic acid resulting nitric oxide toxicity induces aspartoacylase mutations and protein interaction to cause pathophysiology seen in Canavan disease. Med Hypotheses 75:533–534

    Article  CAS  PubMed  Google Scholar 

  143. Surendran S, Bhatnagar M (2011) Upregulation of N-acetylaspartic acid induces oxidative stress to contribute in disease pathophysiology. Int J Neurosci 121:305–309

    Article  CAS  PubMed  Google Scholar 

  144. Francis JS, Strande L, Markov V, Leone P (2012) Aspartoacylase supports oxidative energy metabolism during myelination. J Cereb Blood Flow Metab 32:1725–1736

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  145. Matalon R et al (2000) Knock-out mouse for Canavan disease: a model for gene transfer to the central nervous system. J Gene Med 2:165–175

    Article  CAS  PubMed  Google Scholar 

  146. Ahmed SS et al (2013) A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS gene therapy in Canavan mice. Mol Ther 21:2136–2147

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  147. Traka M et al (2008) Nur7 is a nonsense mutation in the mouse aspartoacylase gene that causes spongy degeneration of the CNS. J Neurosci 28:11537–11549

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  148. Kile BT et al (2003) Functional genetic analysis of mouse chromosome 11. Nature 425:81–86

    Article  CAS  PubMed  Google Scholar 

  149. Carpinelli MR et al (2014) A new mouse model of Canavan leukodystrophy displays hearing impairment due to central nervous system dysmyelination. Dis Model Mech 7(6):649–657

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  150. Kaul R, Gao GP, Balamurugan K, Matalon R (1993) Cloning of the human aspartoacylase cDNA and a common missense mutation in Canavan disease. Nat Genet 5:118–123

    Article  CAS  PubMed  Google Scholar 

  151. Leone P, Janson CG, McPhee SJ, During MJ (1999) Global CNS gene transfer for a childhood neurogenetic enzyme deficiency: Canavan disease. Curr Opin Mol Ther 1:487–492

    CAS  PubMed  Google Scholar 

  152. Leone P et al (2000) Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease. Ann Neurol 48:27–38

    Article  CAS  PubMed  Google Scholar 

  153. Janson C et al (2002) Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain. Hum Gene Ther 13:1391–1412

    Article  CAS  PubMed  Google Scholar 

  154. Matalon R et al (2003) Adeno-associated virus-mediated aspartoacylase gene transfer to the brain of knockout mouse for canavan disease. Mol Ther 7:580–587

    Article  CAS  PubMed  Google Scholar 

  155. McPhee SW et al (2005) Effects of AAV-2-mediated aspartoacylase gene transfer in the tremor rat model of Canavan disease. Brain Res Mol Brain Res 135:112–121

    Article  CAS  PubMed  Google Scholar 

  156. Foust KD et al (2009) Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol 27:59–65

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  157. Leone P et al (2012) Long-term follow-up after gene therapy for canavan disease. Sci Transl Med 4:165ra163

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  158. McPhee SW et al (2006) Immune responses to AAV in a phase I study for Canavan disease. J Gene Med 8:577–588

    Article  CAS  PubMed  Google Scholar 

  159. Ransohoff RM, Brown MA (2012) Innate immunity in the central nervous system. J Clin Invest 122:1164–1171

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  160. Stein-Streilein J, Caspi RR (2014) Immune privilege and the philosophy of immunology. Front Immunol 5:110

    Article  PubMed Central  PubMed  Google Scholar 

  161. Calcedo R, Vandenberghe LH, Gao G, Lin J, Wilson JM (2009) Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J Infect Dis 199:381–390

    Article  PubMed  Google Scholar 

  162. Mingozzi F et al (2013) Prevalence and pharmacological modulation of humoral immunity to AAV vectors in gene transfer to synovial tissue. Gene Ther 20:417–424

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  163. Louis Jeune V, Joergensen JA, Hajjar RJ, Weber T (2013) Pre-existing anti-adeno-associated virus antibodies as a challenge in AAV gene therapy. Hum Gene Ther Methods 24:59–67

    Article  CAS  PubMed  Google Scholar 

  164. Mingozzi F et al (2013) Overcoming preexisting humoral immunity to AAV using capsid decoys. Sci Transl Med 5:194ra192

    Article  CAS  Google Scholar 

  165. Basner-Tschakarjan E, Bijjiga E, Martino AT (2014) Pre-clinical assessment of immune responses to adeno-associated virus (AAV) vectors. Front Immunol 5:28

    PubMed Central  PubMed  Google Scholar 

  166. Sanftner LM et al (2004) Striatal delivery of rAAV-hAADC to rats with preexisting immunity to AAV. Mol Ther 9:403–409

    Article  CAS  PubMed  Google Scholar 

  167. Martino AT et al (2011) The genome of self-complementary adeno-associated viral vectors increases Toll-like receptor 9-dependent innate immune responses in the liver. Blood 117:6459–6468

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  168. Hosel M et al (2012) Toll-like receptor 2-mediated innate immune response in human nonparenchymal liver cells toward adeno-associated viral vectors. Hepatology 55:287–297

    Article  PubMed  CAS  Google Scholar 

  169. Olson JK, Miller SD (2004) Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol 173:3916–3924

    Article  CAS  PubMed  Google Scholar 

  170. Bsibsi M, Ravid R, Gveric D, van Noort JM (2002) Broad expression of Toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol 61:1013–1021

    Article  CAS  PubMed  Google Scholar 

  171. Mingozzi F et al (2007) CD8(+) T-cell responses to adeno-associated virus capsid in humans. Nat Med 13:419–422

    Article  CAS  PubMed  Google Scholar 

  172. Sabatino DE et al (2005) Identification of mouse AAV capsid-specific CD8+ T cell epitopes. Mol Ther 12:1023–1033

    Article  CAS  PubMed  Google Scholar 

  173. Li H et al (2007) Pre-existing AAV capsid-specific CD8+ T cells are unable to eliminate AAV-transduced hepatocytes. Mol Ther 15:792–800

    CAS  PubMed  Google Scholar 

  174. Ciesielska A et al (2013) Cerebral infusion of AAV9 vector-encoding non-self proteins can elicit cell-mediated immune responses. Mol Ther 21:158–166

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  175. Yang B et al (2014) Global CNS transduction of adult mice by intravenously delivered rAAVrh.8 and rAAVrh.10 and nonhuman primates by rAAVrh.10. Mol Ther 22(7):1299–1309

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  176. Zhang H et al (2011) Several rAAV vectors efficiently cross the blood-brain barrier and transduce neurons and astrocytes in the neonatal mouse central nervous system. Mol Ther 19:1440–1448

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  177. Kotterman MA, Schaffer DV (2014) Engineering adeno-associated viruses for clinical gene therapy. Nat Rev Genet 15(7):445–451

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. University of Massachusetts Medical School, 368 Plantation Street, AS6-2049, Worcester, MA, 01605, USA

    Dominic J. Gessler & Guangping Gao

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  1. Dominic J. Gessler
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  2. Guangping Gao
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Correspondence to Guangping Gao .

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  1. Translational Science and Molecular Medicine, Michigan State University, College of Human Science, Grand Rapids, Michigan, USA

    Fredric P. Manfredsson

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Gessler, D.J., Gao, G. (2016). Gene Therapy for the Treatment of Neurological Disorders: Metabolic Disorders. In: Manfredsson, F. (eds) Gene Therapy for Neurological Disorders. Methods in Molecular Biology, vol 1382. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3271-9_30

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  • DOI: https://doi.org/10.1007/978-1-4939-3271-9_30

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