Clinical Gene Therapy Trials for Pompe Disease

  • Cristina Liberati
  • Stephanie Salabarria
  • Manuela Corti
  • Barry J. ByrneEmail author


Pompe disease is a metabolic myopathy which leads to severe and progressive weakness due to glycogen storage in striated muscle and neurons. Generalized weakness leads to cardiopulmonary insufficiency and early mortality. The spectrum of disease ranges from a fatal early-onset form to a more slowly progressive intermediate and adult-onset type. The severity of disease depends on the amount of residual acid α-glucosidase (GAA) activity which is determined by the nature of the two mutant alleles. The lack of GAA leads to accumulation of glycogen in lysosomes of neurons and striated muscle (especially skeletal and cardiac muscle). Lysosomal dysfunction and cellular autophagy result in neuronal cell loss over time. Enzyme replacement therapy (ERT) is the only currently approved treatment for Pompe disease; however, ERT does not effectively address the neural deficits; therefore, alternative approaches using gene therapy must be considered. The principal objective of gene therapy in Pompe disease is to increase the intrinsic ability of the cells to produce GAA. A variety of recombinant adeno-associated viral vectors (rAAV) are being studied to complete this task. The efficacy of gene therapy not only depends on the efficiency of the gene therapy agent but also on the host's immune response. The most critical immunological challenges are anti-AAV capsid antibodies and anti-GAA antibodies. In this chapter, we review the current status of AAV-mediated gene therapy for Pompe disease.


Pompe disease Glycogen storage disorder Gene therapy Clinical trials AAV Immune response 


  1. 1.
    D’Ancona GG, Wurm J, Croce CM (1979) Genetics of type II glycogenosis: assignment of the human gene for acid alpha-glucosidase to chromosome 17. Proc Natl Acad Sci U S A 76(9):4526–4529CrossRefGoogle Scholar
  2. 2.
    Turner SM, Hoyt AK, ElMallah MK, Falk DJ, Byrne BJ, Fuller DD (2016) Neuropathology in respiratory-related motoneurons in young Pompe (Gaa(−/−)) mice. Respir Physiol Neurobiol 227:48–55. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Turner SMF, Falk DJ, Byrne BJ, Fuller DD (2016) Transcriptome assessment of the Pompe (Gaa−/−) mouse spinal cord indicates widespread neuropathology. Physiol Genomics 48(11):785–794. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Reuser AJ, Kroos MA, Hermans MM, Bijvoet AG, Verbeet MP, Van Diggelen OP, Kleijer WJ, Van der Ploeg AT (1995) Glycogenosis type II (acid maltase deficiency). Muscle Nerve Suppl 18(S 14):S61–S69CrossRefGoogle Scholar
  5. 5.
    Ausems MG, ten Berg K, Kroos MA, van Diggelen OP, Wevers RA, Poorthuis BJ, Niezen-Koning KE, van der Ploeg AT, Beemer FA, Reuser AJ, Sandkuijl LA, Wokke JH (1999) Glycogen storage disease type II: birth prevalence agrees with predicted genotype frequency. Community Genet 2(2–3):91–96. CrossRefPubMedGoogle Scholar
  6. 6.
    Lejeune N, Thines-Sempoux D, Hers HG (1963) Tissue fractionation studies. 16. Intracellular distribution and properties of alpha-glucosidases in rat liver. Biochem J 86:16–21CrossRefGoogle Scholar
  7. 7.
    Kishnani PS, Hwu WL, Mandel H, Nicolino M, Yong F, Corzo D, Infantile-Onset Pompe Disease Natural History Study Group (2006) A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. J Pediatr 148(5):671–676. CrossRefPubMedGoogle Scholar
  8. 8.
    Hagemans ML, Laforet P, Hop WJ, Merkies IS, Van Doorn PA, Reuser AJ, Van der Ploeg AT (2007) Impact of late-onset Pompe disease on participation in daily life activities: evaluation of the Rotterdam Handicap Scale. Neuromuscul Disord 17(7):537–543. CrossRefPubMedGoogle Scholar
  9. 9.
    van den Hout HM, Hop W, van Diggelen OP, Smeitink JA, Smit GP, Poll-The BT, Bakker HD, Loonen MC, de Klerk JB, Reuser AJ, van der Ploeg AT (2003) The natural course of infantile Pompe’s disease: 20 original cases compared with 133 cases from the literature. Pediatrics 112(2):332–340CrossRefGoogle Scholar
  10. 10.
    Winkel LP, Hagemans ML, van Doorn PA, Loonen MC, Hop WJ, Reuser AJ, van der Ploeg AT (2005) The natural course of non-classic Pompe’s disease; a review of 225 published cases. J Neurol 252(8):875–884. CrossRefPubMedGoogle Scholar
  11. 11.
    DeRuisseau LR, Fuller DD, Qiu K, DeRuisseau KC, Donnelly WH Jr, Mah C, Reier PJ, Byrne BJ (2009) Neural deficits contribute to respiratory insufficiency in Pompe disease. Proc Natl Acad Sci U S A 106(23):9419–9424. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Gambetti P, DiMauro S, Baker L (1971) Nervous system in Pompe’s disease. Ultrastructure and biochemistry. J Neuropathol Exp Neurol 30(3):412–430CrossRefGoogle Scholar
  13. 13.
    Martini C, Ciana G, Benettoni A, Katouzian F, Severini GM, Bussani R, Bembi B (2001) Intractable fever and cortical neuronal glycogen storage in glycogenosis type 2. Neurology 57(5):906–908CrossRefGoogle Scholar
  14. 14.
    Teng YT, Su WJ, Hou JW, Huang SF (2004) Infantile-onset glycogen storage disease type II (Pompe disease): report of a case with genetic diagnosis and pathological findings. Chang Gung Med J 27(5):379–384PubMedGoogle Scholar
  15. 15.
    Engel AG, Gomez MR, Seybold ME, Lambert EH (1973) The spectrum and diagnosis of acid maltase deficiency. Neurology 23(1):95–106CrossRefGoogle Scholar
  16. 16.
    Pompe Disease Diagnostic Working Group, Winchester B, Bali D, Bodamer OA, Caillaud C, Christensen E, Cooper A, Cupler E, Deschauer M, Fumic K, Jackson M, Kishnani P, Lacerda L, Ledvinova J, Lugowska A, Lukacs Z, Maire I, Mandel H, Mengel E, Muller-Felber W, Piraud M, Reuser A, Rupar T, Sinigerska I, Szlago M, Verheijen F, van Diggelen OP, Wuyts B, Zakharova E, Keutzer J (2008) Methods for a prompt and reliable laboratory diagnosis of Pompe disease: report from an international consensus meeting. Mol Genet Metab 93(3):275–281. CrossRefGoogle Scholar
  17. 17.
    Chen YT, Amalfitano A (2000) Towards a molecular therapy for glycogen storage disease type II (Pompe disease). Mol Med Today 6(6):245–251CrossRefGoogle Scholar
  18. 18.
    Kishnani PS, Howell RR (2004) Pompe disease in infants and children. J Pediatr 144(5 Suppl):S35–S43. CrossRefPubMedGoogle Scholar
  19. 19.
    van der Beek NA, van Capelle CI, van der Velden-van Etten KI, Hop WC, van den Berg B, Reuser AJ, van Doorn PA, van der Ploeg AT, Stam H (2011) Rate of progression and predictive factors for pulmonary outcome in children and adults with Pompe disease. Mol Genet Metab 104(1–2):129–136. CrossRefPubMedGoogle Scholar
  20. 20.
    Hagemans ML, Winkel LP, Van Doorn PA, Hop WJ, Loonen MC, Reuser AJ, Van der Ploeg AT (2005) Clinical manifestation and natural course of late-onset Pompe’s disease in 54 Dutch patients. Brain 128(Pt 3):671–677. CrossRefPubMedGoogle Scholar
  21. 21.
    Muller-Felber W, Horvath R, Gempel K, Podskarbi T, Shin Y, Pongratz D, Walter MC, Baethmann M, Schlotter-Weigel B, Lochmuller H, Schoser B (2007) Late onset Pompe disease: clinical and neurophysiological spectrum of 38 patients including long-term follow-up in 18 patients. Neuromuscul Disord 17(9–10):698–706. CrossRefPubMedGoogle Scholar
  22. 22.
    Byrne BJ, Kishnani PS, Case LE, Merlini L, Muller-Felber W, Prasad S, van der Ploeg A (2011) Pompe disease: design, methodology, and early findings from the Pompe Registry. Mol Genet Metab 103(1):1–11. CrossRefPubMedGoogle Scholar
  23. 23.
    Doucet M, Debigare R, Joanisse DR, Cote C, Leblanc P, Gregoire J, Deslauriers J, Vaillancourt R, Maltais F (2004) Adaptation of the diaphragm and the vastus lateralis in mild-to-moderate COPD. Eur Respir J 24(6):971–979. CrossRefPubMedGoogle Scholar
  24. 24.
    Hermans G, Agten A, Testelmans D, Decramer M, Gayan-Ramirez G (2010) Increased duration of mechanical ventilation is associated with decreased diaphragmatic force: a prospective observational study. Crit Care 14(4):R127. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Hussain SN, Mofarrahi M, Sigala I, Kim HC, Vassilakopoulos T, Maltais F, Bellenis I, Chaturvedi R, Gottfried SB, Metrakos P, Danialou G, Matecki S, Jaber S, Petrof BJ, Goldberg P (2010) Mechanical ventilation-induced diaphragm disuse in humans triggers autophagy. Am J Respir Crit Care Med 182(11):1377–1386. CrossRefPubMedGoogle Scholar
  26. 26.
    Jaber S, Petrof BJ, Jung B, Chanques G, Berthet JP, Rabuel C, Bouyabrine H, Courouble P, Koechlin-Ramonatxo C, Sebbane M, Similowski T, Scheuermann V, Mebazaa A, Capdevila X, Mornet D, Mercier J, Lacampagne A, Philips A, Matecki S (2011) Rapidly progressive diaphragmatic weakness and injury during mechanical ventilation in humans. Am J Respir Crit Care Med 183(3):364–371. CrossRefPubMedGoogle Scholar
  27. 27.
    Levine S, Nguyen T, Taylor N, Friscia ME, Budak MT, Rothenberg P, Zhu J, Sachdeva R, Sonnad S, Kaiser LR, Rubinstein NA, Powers SK, Shrager JB (2008) Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med 358(13):1327–1335. CrossRefPubMedGoogle Scholar
  28. 28.
    Powers SK, Kavazis AN, Levine S (2009) Prolonged mechanical ventilation alters diaphragmatic structure and function. Crit Care Med 37(10 Suppl):S347–S353. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Huang TT, Deoghare HV, Smith BK, Beaver TM, Baker HV, Mehinto AC, Martin AD (2011) Gene expression changes in the human diaphragm after cardiothoracic surgery. J Thorac Cardiovasc Surg 142(5):1214–1222. , 1222 e1211–1220. CrossRefPubMedGoogle Scholar
  30. 30.
    Kurachek SC, Newth CJ, Quasney MW, Rice T, Sachdeva RC, Patel NR, Takano J, Easterling L, Scanlon M, Musa N, Brilli RJ, Wells D, Park GS, Penfil S, Bysani KG, Nares MA, Lowrie L, Billow M, Chiochetti E, Lindgren B (2003) Extubation failure in pediatric intensive care: a multiple-center study of risk factors and outcomes. Crit Care Med 31(11):2657–2664. CrossRefPubMedGoogle Scholar
  31. 31.
    Levine S, Kaiser L, Leferovich J, Tikunov B (1997) Cellular adaptations in the diaphragm in chronic obstructive pulmonary disease. N Engl J Med 337(25):1799–1806. CrossRefPubMedGoogle Scholar
  32. 32.
    Lindsay DC, Lovegrove CA, Dunn MJ, Bennett JG, Pepper JR, Yacoub MH, Poole-Wilson PA (1996) Histological abnormalities of muscle from limb, thorax and diaphragm in chronic heart failure. Eur Heart J 17(8):1239–1250CrossRefGoogle Scholar
  33. 33.
    Macgowan NA, Evans KG, Road JD, Reid WD (2001) Diaphragm injury in individuals with airflow obstruction. Am J Respir Crit Care Med 163(7):1654–1659. CrossRefPubMedGoogle Scholar
  34. 34.
    Mercadier JJ, Schwartz K, Schiaffino S, Wisnewsky C, Ausoni S, Heimburger M, Marrash R, Pariente R, Aubier M (1998) Myosin heavy chain gene expression changes in the diaphragm of patients with chronic lung hyperinflation. Am J Phys 274(4 Pt 1):L527–L534Google Scholar
  35. 35.
    Nguyen T, Rubinstein NA, Vijayasarathy C, Rome LC, Kaiser LR, Shrager JB, Levine S (2005) Effect of chronic obstructive pulmonary disease on calcium pump ATPase expression in human diaphragm. J Appl Physiol (1985) 98(6):2004–2010. CrossRefGoogle Scholar
  36. 36.
    Ottenheijm CA, Heunks LM, Dekhuijzen PN (2007) Diaphragm muscle fiber dysfunction in chronic obstructive pulmonary disease: toward a pathophysiological concept. Am J Respir Crit Care Med 175(12):1233–1240. CrossRefPubMedGoogle Scholar
  37. 37.
    Levine S, Gregory C, Nguyen T, Shrager J, Kaiser L, Rubinstein N, Dudley G (2002) Bioenergetic adaptation of individual human diaphragmatic myofibers to severe COPD. J Appl Physiol (1985) 92(3):1205–1213. CrossRefGoogle Scholar
  38. 38.
    Howell RR, Byrne B, Darras BT, Kishnani P, Nicolino M, van der Ploeg A (2006) Diagnostic challenges for Pompe disease: an under-recognized cause of floppy baby syndrome. Genet Med 8(5):289–296CrossRefGoogle Scholar
  39. 39.
    Chamoles NA, Niizawa G, Blanco M, Gaggioli D, Casentini C (2004) Glycogen storage disease type II: enzymatic screening in dried blood spots on filter paper. Clin Chim Acta 347(1–2):97–102. CrossRefPubMedGoogle Scholar
  40. 40.
    Chien YH, Chiang SC, Zhang XK, Keutzer J, Lee NC, Huang AC, Chen CA, Wu MH, Huang PH, Tsai FJ, Chen YT, Hwu WL (2008) Early detection of Pompe disease by newborn screening is feasible: results from the Taiwan screening program. Pediatrics 122(1):e39–e45. CrossRefPubMedGoogle Scholar
  41. 41.
    Parkinson-Lawrence E, Fuller M, Hopwood JJ, Meikle PJ, Brooks DA (2006) Immunochemistry of lysosomal storage disorders. Clin Chem 52(9):1660–1668. CrossRefPubMedGoogle Scholar
  42. 42.
    Chien YH, Lee NC, Huang HJ, Thurberg BL, Tsai FJ, Hwu WL (2011) Later-onset Pompe disease: early detection and early treatment initiation enabled by newborn screening. J Pediatr 158(6):1023–1027. e1021. CrossRefPubMedGoogle Scholar
  43. 43.
    Angelini C, Semplicini C, Ravaglia S, Bembi B, Servidei S, Pegoraro E, Moggio M, Filosto M, Sette E, Crescimanno G, Tonin P, Parini R, Morandi L, Marrosu G, Greco G, Musumeci O, Di Iorio G, Siciliano G, Donati MA, Carubbi F, Ermani M, Mongini T, Toscano A, Italian GG (2012) Observational clinical study in juvenile-adult glycogenosis type 2 patients undergoing enzyme replacement therapy for up to 4 years. J Neurol 259(5):952–958. CrossRefPubMedGoogle Scholar
  44. 44.
    Regnery C, Kornblum C, Hanisch F, Vielhaber S, Strigl-Pill N, Grunert B, Muller-Felber W, Glocker FX, Spranger M, Deschauer M, Mengel E, Schoser B (2012) 36 months observational clinical study of 38 adult Pompe disease patients under alglucosidase alfa enzyme replacement therapy. J Inherit Metab Dis 35(5):837–845. CrossRefPubMedGoogle Scholar
  45. 45.
    Strothotte S, Strigl-Pill N, Grunert B, Kornblum C, Eger K, Wessig C, Deschauer M, Breunig F, Glocker FX, Vielhaber S, Brejova A, Hilz M, Reiners K, Muller-Felber W, Mengel E, Spranger M, Schoser B (2010) Enzyme replacement therapy with alglucosidase alfa in 44 patients with late-onset glycogen storage disease type 2: 12-month results of an observational clinical trial. J Neurol 257(1):91–97. CrossRefPubMedGoogle Scholar
  46. 46.
    van Capelle CI, Winkel LP, Hagemans ML, Shapira SK, Arts WF, van Doorn PA, Hop WC, Reuser AJ, van der Ploeg AT (2008) Eight years experience with enzyme replacement therapy in two children and one adult with Pompe disease. Neuromuscul Disord 18(6):447–452. CrossRefPubMedGoogle Scholar
  47. 47.
    Bembi B, Pisa FE, Confalonieri M, Ciana G, Fiumara A, Parini R, Rigoldi M, Moglia A, Costa A, Carlucci A, Danesino C, Pittis MG, Dardis A, Ravaglia S (2010) Long-term observational, non-randomized study of enzyme replacement therapy in late-onset glycogenosis type II. J Inherit Metab Dis 33(6):727–735. CrossRefPubMedGoogle Scholar
  48. 48.
    Raben N, Danon M, Gilbert AL, Dwivedi S, Collins B, Thurberg BL, Mattaliano RJ, Nagaraju K, Plotz PH (2003) Enzyme replacement therapy in the mouse model of Pompe disease. Mol Genet Metab 80(1–2):159–169CrossRefGoogle Scholar
  49. 49.
    Kikuchi T, Yang HW, Pennybacker M, Ichihara N, Mizutani M, Van Hove JL, Chen YT (1998) Clinical and metabolic correction of pompe disease by enzyme therapy in acid maltase-deficient quail. J Clin Invest 101(4):827–833. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Mancall EL, Aponte GE, Berry RG (1965) Pompe’s disease (diffuse glycogenosis) with neuronal storage. J Neuropathol Exp Neurol 24:85–96CrossRefGoogle Scholar
  51. 51.
    Van den Hout JM, Kamphoven JH, Winkel LP, Arts WF, De Klerk JB, Loonen MC, Vulto AG, Cromme-Dijkhuis A, Weisglas-Kuperus N, Hop W, Van Hirtum H, Van Diggelen OP, Boer M, Kroos MA, Van Doorn PA, Van der Voort E, Sibbles B, Van Corven EJ, Brakenhoff JP, Van Hove J, Smeitink JA, de Jong G, Reuser AJ, Van der Ploeg AT (2004) Long-term intravenous treatment of Pompe disease with recombinant human alpha-glucosidase from milk. Pediatrics 113(5):e448–e457CrossRefGoogle Scholar
  52. 52.
    Banugaria SG, Prater SN, Ng YK, Kobori JA, Finkel RS, Ladda RL, Chen YT, Rosenberg AS, Kishnani PS (2011) The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: lessons learned from infantile Pompe disease. Genet Med 13(8):729–736. CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Kishnani PS, Goldenberg PC, DeArmey SL, Heller J, Benjamin D, Young S, Bali D, Smith SA, Li JS, Mandel H, Koeberl D, Rosenberg A, Chen YT (2010) Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants. Mol Genet Metab 99(1):26–33. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Amalfitano A, Bengur AR, Morse RP, Majure JM, Case LE, Veerling DL, Mackey J, Kishnani P, Smith W, McVie-Wylie A, Sullivan JA, Hoganson GE, Phillips JA 3rd, Schaefer GB, Charrow J, Ware RE, Bossen EH, Chen YT (2001) Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial. Genet Med 3(2):132–138PubMedGoogle Scholar
  55. 55.
    Berrier KL, Kazi ZB, Prater SN, Bali DS, Goldstein J, Stefanescu MC, Rehder CW, Botha EG, Ellaway C, Bhattacharya K, Tylki-Szymanska A, Karabul N, Rosenberg AS, Kishnani PS (2015) CRIM-negative infantile Pompe disease: characterization of immune responses in patients treated with ERT monotherapy. Genet Med 17(11):912–918. CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Berrier KL, Kazi ZB, Prater SN, Bali DS, Goldstein J, Stefanescu MC, Rehder CW, Botha EG, Ellaway C, Bhattacharya K, Tylki-Szymanska A, Karabul N, Rosenberg AS, Kishnani PS (2015) CORRIGENDUM: CRIM-negative infantile Pompe disease: characterization of immune responses in patients treated with ERT monotherapy. Genet Med 17(7):596. CrossRefPubMedGoogle Scholar
  57. 57.
    Banugaria SG, Prater SN, Patel TT, Dearmey SM, Milleson C, Sheets KB, Bali DS, Rehder CW, Raiman JA, Wang RA, Labarthe F, Charrow J, Harmatz P, Chakraborty P, Rosenberg AS, Kishnani PS (2013) Algorithm for the early diagnosis and treatment of patients with cross reactive immunologic material-negative classic infantile pompe disease: a step towards improving the efficacy of ERT. PLoS One 8(6):e67052. CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Mendelsohn NJ, Messinger YH, Rosenberg AS, Kishnani PS (2009) Elimination of antibodies to recombinant enzyme in Pompe’s disease. N Engl J Med 360(2):194–195. CrossRefPubMedGoogle Scholar
  59. 59.
    Messinger YH, Mendelsohn NJ, Rhead W, Dimmock D, Hershkovitz E, Champion M, Jones SA, Olson R, White A, Wells C, Bali D, Case LE, Young SP, Rosenberg AS, Kishnani PS (2012) Successful immune tolerance induction to enzyme replacement therapy in CRIM-negative infantile Pompe disease. Genet Med 14(1):135–142. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Sun B, Kulis MD, Young SP, Hobeika AC, Li S, Bird A, Zhang H, Li Y, Clay TM, Burks W, Kishnani PS, Koeberl DD (2010) Immunomodulatory gene therapy prevents antibody formation and lethal hypersensitivity reactions in murine Pompe disease. Mol Ther 18(2):353–360. CrossRefPubMedGoogle Scholar
  61. 61.
    Franco LM, Sun B, Yang X, Bird A, Zhang H, Schneider A, Brown T, Young SP, Clay TM, Amalfitano A, Chen YT, Koeberl DD (2005) Evasion of immune responses to introduced human acid alpha-glucosidase by liver-restricted expression in glycogen storage disease type II. Mol Ther 12(5):876–884. CrossRefPubMedGoogle Scholar
  62. 62.
    Wang G, Young SP, Bali D, Hutt J, Li S, Benson J, Koeberl DD (2014) Assessment of toxicity and biodistribution of recombinant AAV8 vector-mediated immunomodulatory gene therapy in mice with Pompe disease. Mol Ther Methods Clin Dev 1:14018. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Elder ME, Nayak S, Collins SW, Lawson LA, Kelley JS, Herzog RW, Modica RF, Lew J, Lawrence RM, Byrne BJ (2013) B-Cell depletion and immunomodulation before initiation of enzyme replacement therapy blocks the immune response to acid alpha-glucosidase in infantile-onset Pompe disease. J Pediatr 163(3):847–854. e841. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Calcedo R, Morizono H, Wang L, McCarter R, He J, Jones D, Batshaw ML, Wilson JM (2011) Adeno-associated virus antibody profiles in newborns, children, and adolescents. Clin Vaccine Immunol 18(9):1586–1588. CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Li C, Narkbunnam N, Samulski RJ, Asokan A, Hu G, Jacobson LJ, Manco-Johnson MJ, Monahan PE, Joint Outcome Study Investigators (2012) Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia. Gene Ther 19(3):288–294. CrossRefPubMedGoogle Scholar
  66. 66.
    Erles K, Sebokova P, Schlehofer JR (1999) Update on the prevalence of serum antibodies (IgG and IgM) to adeno-associated virus (AAV). J Med Virol 59(3):406–411CrossRefGoogle Scholar
  67. 67.
    Hauck B, Murphy SL, Smith PH, Qu G, Liu X, Zelenaia O, Mingozzi F, Sommer JM, High KA, Wright JF (2009) Undetectable transcription of cap in a clinical AAV vector: implications for preformed capsid in immune responses. Mol Ther 17(1):144–152. CrossRefPubMedGoogle Scholar
  68. 68.
    Mingozzi F, High KA (2007) Immune responses to AAV in clinical trials. Curr Gene Ther 7(5):316–324CrossRefGoogle Scholar
  69. 69.
    Mingozzi F, High KA (2011) Immune responses to AAV in clinical trials. Curr Gene Ther 11(4):321–330CrossRefGoogle Scholar
  70. 70.
    Mingozzi F, High KA (2013) Immune responses to AAV vectors: overcoming barriers to successful gene therapy. Blood 122(1):23–36. CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Corti M, Cleaver B, Clement N, Conlon TJ, Faris KJ, Wang G, Benson J, Tarantal AF, Fuller D, Herzog RW, Byrne BJ (2015) Evaluation of readministration of a recombinant adeno-associated virus vector expressing acid alpha-glucosidase in Pompe disease: preclinical to clinical planning. Hum Gene Ther Clin Dev 26(3):185–193. CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Calcedo R, Wilson JM (2013) Humoral immune response to AAV. Front Immunol 4:341. CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Corti M, Elder M, Falk D, Lawson L, Smith B, Nayak S, Conlon T, Clement N, Erger K, Lavassani E, Green M, Doerfler P, Herzog R, Byrne B (2014) B-cell depletion is protective against anti-AAV capsid immune response: a human subject case study. Mol Ther Methods Clin Dev 1.
  74. 74.
    Smith BK, Collins SW, Conlon TJ, Mah CS, Lawson LA, Martin AD, Fuller DD, Cleaver BD, Clement N, Phillips D, Islam S, Dobjia N, Byrne BJ (2013) Phase I/II trial of adeno-associated virus-mediated alpha-glucosidase gene therapy to the diaphragm for chronic respiratory failure in Pompe disease: initial safety and ventilatory outcomes. Hum Gene Ther 24(6):630–640. CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Corti M, Liberati C, Smith BK, Lawson LA, Tuna IS, Conlon TJ, Erger KE, Islam S, Herzog R, Fuller DD, Collins S, Byrne BJ (2017) Safety of intradiaphragmatic delivery of adeno-associated virus-mediated alpha-glucosidase (rAAV1-CMV-hGAA) gene therapy in children affected by Pompe disease. Hum Gene Ther Clin Dev.
  76. 76.
    Byrne PI, Collins S, Mah CC, Smith B, Conlon T, Martin SD, Corti M, Cleaver B, Islam S, Lawson LA (2014) Phase I/II trial of diaphragm delivery of recombinant adeno-associated virus acid alpha-glucosidase (rAAaV1-CMV-GAA) gene vector in patients with Pompe disease. Hum Gene Ther Clin Dev 25(3):134–163. CrossRefPubMedGoogle Scholar
  77. 77.
    Raben N, Nagaraju K, Lee E, Kessler P, Byrne B, Lee L, LaMarca M, King C, Ward J, Sauer B, Plotz P (1998) Targeted disruption of the acid alpha-glucosidase gene in mice causes an illness with critical features of both infantile and adult human glycogen storage disease type II. J Biol Chem 273(30):19086–19092CrossRefGoogle Scholar
  78. 78.
    Hermonat PL, Muzyczka N (1984) Use of adeno-associated virus as a mammalian DNA cloning vector: transduction of neomycin resistance into mammalian tissue culture cells. Proc Natl Acad Sci U S A 81(20):6466–6470CrossRefGoogle Scholar
  79. 79.
    Hermonat PL, Labow MA, Wright R, Berns KI, Muzyczka N (1984) Genetics of adeno-associated virus: isolation and preliminary characterization of adeno-associated virus type 2 mutants. J Virol 51(2):329–339PubMedPubMedCentralGoogle Scholar
  80. 80.
    Samulski RJ, Chang LS, Shenk T (1987) A recombinant plasmid from which an infectious adeno-associated virus genome can be excised in vitro and its use to study viral replication. J Virol 61(10):3096–3101PubMedPubMedCentralGoogle Scholar
  81. 81.
    Doerfler PA, Todd AG, Clement N, Falk DJ, Nayak S, Herzog RW, Byrne BJ (2016) Copackaged AAV9 vectors promote simultaneous immune tolerance and phenotypic correction of Pompe disease. Hum Gene Ther 27(1):43–59. CrossRefPubMedGoogle Scholar
  82. 82.
    Amalfitano A, McVie-Wylie AJ, Hu H, Dawson TL, Raben N, Plotz P, Chen YT (1999) Systemic correction of the muscle disorder glycogen storage disease type II after hepatic targeting of a modified adenovirus vector encoding human acid-alpha-glucosidase. Proc Natl Acad Sci U S A 96(16):8861–8866CrossRefGoogle Scholar
  83. 83.
    Zaretsky JZ, Candotti F, Boerkoel C, Adams EM, Yewdell JW, Blaese RM, Plotz PH (1997) Retroviral transfer of acid alpha-glucosidase cDNA to enzyme-deficient myoblasts results in phenotypic spread of the genotypic correction by both secretion and fusion. Hum Gene Ther 8(13):1555–1563. CrossRefPubMedGoogle Scholar
  84. 84.
    Raben N, Plotz P, Byrne BJ (2002) Acid alpha-glucosidase deficiency (glycogenosis type II, Pompe disease). Curr Mol Med 2(2):145–166CrossRefGoogle Scholar
  85. 85.
    Nicolino MP, Puech JP, Kremer EJ, Reuser AJ, Mbebi C, Verdiere-Sahuque M, Kahn A, Poenaru L (1998) Adenovirus-mediated transfer of the acid alpha-glucosidase gene into fibroblasts, myoblasts and myotubes from patients with glycogen storage disease type II leads to high level expression of enzyme and corrects glycogen accumulation. Hum Mol Genet 7(11):1695–1702CrossRefGoogle Scholar
  86. 86.
    Pauly DF, Johns DC, Matelis LA, Lawrence JH, Byrne BJ, Kessler PD (1998) Complete correction of acid alpha-glucosidase deficiency in Pompe disease fibroblasts in vitro, and lysosomally targeted expression in neonatal rat cardiac and skeletal muscle. Gene Ther 5(4):473–480. CrossRefPubMedGoogle Scholar
  87. 87.
    Pauly DF, Fraites TJ, Toma C, Bayes HS, Huie ML, Hirschhorn R, Plotz PH, Raben N, Kessler PD, Byrne BJ (2001) Intercellular transfer of the virally derived precursor form of acid alpha-glucosidase corrects the enzyme deficiency in inherited cardioskeletal myopathy Pompe disease. Hum Gene Ther 12(5):527–538. CrossRefPubMedGoogle Scholar
  88. 88.
    Falk DJ, Todd AG, Lee S, Soustek MS, ElMallah MK, Fuller DD, Notterpek L, Byrne BJ (2015) Peripheral nerve and neuromuscular junction pathology in Pompe disease. Hum Mol Genet 24(3):625–636. CrossRefPubMedGoogle Scholar
  89. 89.
    Fuller DD, ElMallah MK, Smith BK, Corti M, Lawson LA, Falk DJ, Byrne BJ (2013) The respiratory neuromuscular system in Pompe disease. Respir Physiol Neurobiol 189(2):241–249. CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Mah C, Pacak CA, Cresawn KO, Deruisseau LR, Germain S, Lewis MA, Cloutier DA, Fuller DD, Byrne BJ (2007) Physiological correction of Pompe disease by systemic delivery of adeno-associated virus serotype 1 vectors. Mol Ther 15(3):501–507. CrossRefPubMedGoogle Scholar
  91. 91.
    Mah C, Cresawn KO, Fraites TJ Jr, Pacak CA, Lewis MA, Zolotukhin I, Byrne BJ (2005) Sustained correction of glycogen storage disease type II using adeno-associated virus serotype 1 vectors. Gene Ther 12(18):1405–1409. CrossRefPubMedGoogle Scholar
  92. 92.
    Pacak CA, Mah CS, Thattaliyath BD, Conlon TJ, Lewis MA, Cloutier DE, Zolotukhin I, Tarantal AF, Byrne BJ (2006) Recombinant adeno-associated virus serotype 9 leads to preferential cardiac transduction in vivo. Circ Res 99(4):e3–e9. CrossRefPubMedGoogle Scholar
  93. 93.
    Sun B, Zhang H, Franco LM, Young SP, Schneider A, Bird A, Amalfitano A, Chen YT, Koeberl DD (2005) Efficacy of an adeno-associated virus 8-pseudotyped vector in glycogen storage disease type II. Mol Ther 11(1):57–65. CrossRefPubMedGoogle Scholar
  94. 94.
    Fraites TJ Jr, Schleissing MR, Shanely RA, Walter GA, Cloutier DA, Zolotukhin I, Pauly DF, Raben N, Plotz PH, Powers SK, Kessler PD, Byrne BJ (2002) Correction of the enzymatic and functional deficits in a model of Pompe disease using adeno-associated virus vectors. Mol Ther 5(5 Pt 1):571–578. CrossRefPubMedGoogle Scholar
  95. 95.
    Sun B, Young SP, Li P, Di C, Brown T, Salva MZ, Li S, Bird A, Yan Z, Auten R, Hauschka SD, Koeberl DD (2008) Correction of multiple striated muscles in murine Pompe disease through adeno-associated virus-mediated gene therapy. Mol Ther 16(8):1366–1371. CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Mah C, Fraites TJ Jr, Cresawn KO, Zolotukhin I, Lewis MA, Byrne BJ (2004) A new method for recombinant adeno-associated virus vector delivery to murine diaphragm. Mol Ther 9(3):458–463. CrossRefPubMedGoogle Scholar
  97. 97.
    Rucker M, Fraites TJ Jr, Porvasnik SL, Lewis MA, Zolotukhin I, Cloutier DA, Byrne BJ (2004) Rescue of enzyme deficiency in embryonic diaphragm in a mouse model of metabolic myopathy: Pompe disease. Development 131(12):3007–3019. CrossRefPubMedGoogle Scholar
  98. 98.
    Mah CS, Falk DJ, Germain SA, Kelley JS, Lewis MA, Cloutier DA, DeRuisseau LR, Conlon TJ, Cresawn KO, Fraites TJ Jr, Campbell-Thompson M, Fuller DD, Byrne BJ (2010) Gel-mediated delivery of AAV1 vectors corrects ventilatory function in Pompe mice with established disease. Mol Ther 18(3):502–510. CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Conlon TJ, Erger K, Porvasnik S, Cossette T, Roberts C, Combee L, Islam S, Kelley J, Cloutier D, Clement N, Abernathy CR, Byrne BJ (2013) Preclinical toxicology and biodistribution studies of recombinant adeno-associated virus 1 human acid alpha-glucosidase. Hum Gene Ther Clin Dev 24(3):127–133. CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Sidman RL, Taksir T, Fidler J, Zhao M, Dodge JC, Passini MA, Raben N, Thurberg BL, Cheng SH, Shihabuddin LS (2008) Temporal neuropathologic and behavioral phenotype of 6neo/6neo Pompe disease mice. J Neuropathol Exp Neurol 67(8):803–818. CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Rabinowitz JE, Rolling F, Li C, Conrath H, Xiao W, Xiao X, Samulski RJ (2002) Cross-packaging of a single adeno-associated virus (AAV) type 2 vector genome into multiple AAV serotypes enables transduction with broad specificity. J Virol 76(2):791–801CrossRefGoogle Scholar
  102. 102.
    Chao H, Liu Y, Rabinowitz J, Li C, Samulski RJ, Walsh CE (2000) Several log increase in therapeutic transgene delivery by distinct adeno-associated viral serotype vectors. Mol Ther 2(6):619–623. CrossRefPubMedGoogle Scholar
  103. 103.
    Chao H, Monahan PE, Liu Y, Samulski RJ, Walsh CE (2001) Sustained and complete phenotype correction of hemophilia B mice following intramuscular injection of AAV1 serotype vectors. Mol Ther 4(3):217–222. CrossRefPubMedGoogle Scholar
  104. 104.
    Falk DJ, Soustek MS, Todd AG, Mah CS, Cloutier DA, Kelley JS, Clement N, Fuller DD, Byrne BJ (2015) Comparative impact of AAV and enzyme replacement therapy on respiratory and cardiac function in adult Pompe mice. Mol Ther Methods Clin Dev 2:15007. CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Han SO, Ronzitti G, Arnson B, Leborgne C, Li S, Mingozzi F, Koeberl D (2017) Low-dose liver-targeted gene therapy for Pompe disease enhances therapeutic efficacy of ERT via immune tolerance induction. Mol Ther Methods Clin Dev 4:126–136. CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Doerfler PA, Nayak S, Corti M, Morel L, Herzog RW, Byrne BJ (2016) Targeted approaches to induce immune tolerance for Pompe disease therapy. Mol Ther Methods Clin Dev 3:15053. CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Nayak S, Doerfler PA, Porvasnik SL, Cloutier DD, Khanna R, Valenzano KJ, Herzog RW, Byrne BJ (2014) Immune responses and hypercoagulation in ERT for Pompe disease are mutation and rhGAA dose dependent. PLoS One 9(6):e98336. CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Smith BK, Martin AD, Lawson LA, Vernot V, Marcus J, Islam S, Shafi N, Corti M, Collins SW, Byrne BJ (2017) Inspiratory muscle conditioning exercise and diaphragm gene therapy in Pompe disease: clinical evidence of respiratory plasticity. Exp Neurol 287(Pt 2):216–224. CrossRefPubMedGoogle Scholar
  109. 109.
    Byrne BJ, Falk DJ, Pacak CA, Nayak S, Herzog RW, Elder ME, Collins SW, Conlon TJ, Clement N, Cleaver BD, Cloutier DA, Porvasnik SL, Islam S, Elmallah MK, Martin A, Smith BK, Fuller DD, Lawson LA, Mah CS (2011) Pompe disease gene therapy. Hum Mol Genet 20(R1):R61–R68. CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Brantly ML, Chulay JD, Wang L, Mueller C, Humphries M, Spencer LT, Rouhani F, Conlon TJ, Calcedo R, Betts MR, Spencer C, Byrne BJ, Wilson JM, Flotte TR (2009) Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy. Proc Natl Acad Sci U S A 106(38):16363–16368. CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Mendell JR, Rodino-Klapac LR, Rosales XQ, Coley BD, Galloway G, Lewis S, Malik V, Shilling C, Byrne BJ, Conlon T, Campbell KJ, Bremer WG, Taylor LE, Flanigan KM, Gastier-Foster JM, Astbury C, Kota J, Sahenk Z, Walker CM, Clark KR (2010) Sustained alpha-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D. Ann Neurol 68(5):629–638. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Cristina Liberati
    • 1
  • Stephanie Salabarria
    • 1
  • Manuela Corti
    • 1
    • 2
  • Barry J. Byrne
    • 1
    • 2
    Email author
  1. 1.Department of Pediatrics, College of MedicineUniversity of FloridaGainesvilleUSA
  2. 2.Powell Gene Therapy CenterUniversity of FloridaGainesvilleUSA

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