Setting Back the Clock: Adenoviral-Mediated Gene Therapy for Lysosomal Storage Disorders

  • Dolan Sondhi
  • Neil R. Hackett
  • Stephen M. Kaminksy
  • Ronald G. Crystal

Lysosomal storage diseases (LSD) arise from mutations in the genes for lysosomal proteins that degrade and recycle macromolecules (Futerman and van Meer, 2004; Mach, 2002; Vellodi, 2005; Walkley, 2001). The undegraded waste products accumulate over time, resulting in derangement of cell physiology and eventually cell death. It follows, therefore, that delivery and expression of a wild-type copy of the defective gene to the affected cells should be preventive or therapeutic. For the lysosomal storage disorders, the challenges for gene therapy are to deliver the gene to the target tissue and to achieve reduction of “lysosomal storage,” thus preserving cellular function.

Of the various strategies to achieve that goal, replication-deficient adenovirusderived vectors (Ad) are generally thought to be inappropriate because although Ad vectors mediate high levels of production of their transgene, expression is transient over a period of only a few weeks (Hackett and Crystal, 2003; Trapnell and Gorziglia, 1994; Wilson, 1996). This chapter provides a contrary and counterintuitive view, making the case for using Ad vectors to treat the lysosomal storage disorders. We do so by first providing an overview of the production and properties of Ad vectors and then discussing studies in which Ad has been used to treat animal models of lysosomal storage diseases. The intent of this analysis is to critically evaluate the applicability of Ad for the challenges provided by LSD, including the required spatial and temporal pattern of gene expression. We then discuss a novel hypothesis, which we call “setting back the clock,” which holds that, for some lysosomal storage diseases, transient overexpression of the deficient gene at high levels may be sufficient to completely reverse the storage defect and may give a substantial benefit, especially in diseases where the accumulation of the storage defect is slow.


Fabry Disease Pompe Disease Therapeutic Gene Lysosomal Storage Disorder Lysosomal Storage Disease 


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  1. Bennett, J., Wilson, J., Sun, D., Forbes, B., and Maguire, A., 1994, Adenovirus vector-mediated in vivo gene transfer into adult murine retina, Invest Ophthalmol. Vis. Sci. 35: 2535.Google Scholar
  2. Brough, D.E., Hsu, C., Kulesa, V.A., Lee, G.M., Cantolupo, L.J., Lizonova, A., and Kovesdi, I., 1997, Activation of transgene expression by early region 4 is responsible for a high level of persistent transgene expression from adenovirus vectors in vivo, J. Virol. 71: 9206.PubMedGoogle Scholar
  3. Chaum, E. and Hatton, M.P., 2002, Gene therapy for genetic and acquired retinal diseases, Surv. Ophthalmol. 47: 449.CrossRefPubMedGoogle Scholar
  4. Chou, J.Y., Zingone, A., and Pan, C.J., 2002, Adenovirus-mediated gene therapy in a mouse model of glycogen storage disease type 1a, Eur. J. Pediatr. 161 Suppl 1: S56.PubMedGoogle Scholar
  5. Cohen, C.J., Xiang, Z.Q., Gao, G.P., Ertl, H.C., Wilson, J.M., and Bergelson, J.M., 2002, Chimpanzee adenovirus CV-68 adapted as a gene delivery vector interacts with the coxsackievirus and adenovirus receptor, J. Gen. Virol. 83: 151.PubMedGoogle Scholar
  6. Crystal, R.G., 1995, Transfer of genes to humans: Early lessons and obstacles to success, Science 270: 404.CrossRefPubMedGoogle Scholar
  7. Crystal, R.G., Harvey, B.G., Wisnivesky, J.P., O’Donoghue, K.A., Chu, K.W., Maroni, J., Muscat, J.C., Pippo, A.L., Wright, C.E., Kaner, R.J., Leopold, P.L., Kessler, P.D., Rasmussen, H.S., Rosengart, T.K., and Hollmann, C., 2002, Analysis of risk factors for local delivery of low- and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of comorbid conditions, Hum. Gene Ther. 13: 65.CrossRefPubMedGoogle Scholar
  8. Desnick, R.J. and Schuchman, E.H., 2002, Enzyme replacement and enhancement therapies: lessons from lysosomal disorders, Nat. Rev. Genet. 3: 954.CrossRefPubMedGoogle Scholar
  9. Ding, E.Y., Hodges, B.L., Hu, H., McVie-Wylie, A.J., Serra, D., Migone, F.K., Pressley, D., Chen, Y.T., and Amalfitano, A., 2001, Long-term efficacy after [E1-, polymerase-] adenovirus-mediated transfer of human acid-alpha-glucosidase gene into glycogen storage disease type II knockout mice, Hum. Gene Ther 12: 955.CrossRefPubMedGoogle Scholar
  10. Du, H., Heur, M., Witte, D.P., Ameis, D., and Grabowski, G.A., 2002, Lysosomal acid lipase deficiency: Correction of lipid storage by adenovirus-mediated gene transfer in mice, Hum. Gene Ther 13: 1361.CrossRefPubMedGoogle Scholar
  11. Engelhardt, J.F., Ye, X., Doranz, B., and Wilson, J.M., 1994, Ablation of E2A in recombinant adenoviruses improves transgene persistence and decreases inflammatory response in mouse liver, Proc. Natl. Acad Sci USA. 91: 6196.CrossRefPubMedGoogle Scholar
  12. Futerman, A.H. and van Meer, G., 2004, The cell biology of lysosomal storage disorders, Nat. Rev. Mol. Cell Biol. 5: 554.CrossRefPubMedGoogle Scholar
  13. Gao, G.P., Yang, Y., and Wilson, J.M., 1996, Biology of adenovirus vectors with E1 and E4 deletions for liver-directed gene therapy, J. Virol 70: 8934.PubMedGoogle Scholar
  14. Ghodsi, A., Stein, C., Derksen, T., Martins, I., Anderson, R.D., and Davidson, B.L., 1999, Systemic hyperosmolality improves beta-glucuronidase distribution and pathology in murine MPS VII brain following intraventricular gene transfer, Exp. Neurol. 160: 109.CrossRefPubMedGoogle Scholar
  15. Graham, F.L. and Prevec, L., 1995, Methods for construction of adenovirus vectors, Mol. Biotechnol. Jun, 3: 207.Google Scholar
  16. Graham, F.L., Smiley, J., Russell, W.C., and Nairn, R., 1977, Characteristics of a human cell line transformed by DNA from human adenovirus type 5, J. Gen. Virol. 36: 59.CrossRefPubMedGoogle Scholar
  17. Guibinga, G.H., Lochmuller, H., Massie, B., Nalbantoglu, J., Karpati, G., and Petrof, B.J., 1998, Combinatorial blockade of calcineurin and CD28 signaling facilitates primary and secondary therapeutic gene transfer by adenovirus vectors in dystrophic (mdx) mouse muscles, J. Virol 72: 4601.PubMedGoogle Scholar
  18. Guidotti, J.E., Mignon, A., Haase, G., Caillaud, C., McDonell, N., Kahn, A., and Poenaru, L., 1999, Adenoviral gene therapy of the Tay-Sachs disease in hexosa-minidase A-deficient knock-out mice, Hum. Mol. Genet. 8: 831.CrossRefPubMedGoogle Scholar
  19. Hackett, N.R. and Crystal, R.G., 2003, Adenovirus vectors for gene therapy. In Gene and Cell Therapy: Therapeutic Mechanisms and Strategies (Ed. N. Smyth Templeton). Marcel Dekker, New York, pp. 17-42.Google Scholar
  20. Hackett, N.R., El Sawy, T., Lee, L.Y., Silva, I., O’Leary, J., Rosengart, T.K., and Crystal, R.G., 2000, Use of quantitative TaqMan real-time PCR to track the time-dependent distribution of gene transfer vectors in vivo, Mol. Ther. 2: 649.CrossRefPubMedGoogle Scholar
  21. Harvey, B.G., Maroni, J., O’Donoghue, K.A., Chu, K.W., Muscat, J.C., Pippo, A.L., Wright, C.E., Hollmann, C., Wisnivesky, J.P., Kessler, P.D., Rasmussen, H.S., Rosengart, T.K., and Crystal, R.G., 2002, Safety of local delivery of low- and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of morbid conditions, Hum. Gene Ther. 13: 15.CrossRefPubMedGoogle Scholar
  22. Horwitz, M.S., 1996, Adenoviruses. In Fields Virology (Eds. B.N. Fields, D.M. Knipe, and P.M. Howley), Philadelphia: Lippincott-Raven, pp. 2149-2171.Google Scholar
  23. Kamata, Y., Tanabe, A., Kanaji, A., Kosuga, M., Fukuhara, Y., Li, X.K., Suzuki, S., Yamada, M., Azuma, N., and Okuyama, T., 2003, Long-term normalization in the central nervous system, ocular manifestations, and skeletal deformities by a single systemic adenovirus injection into neonatal mice with mucopolysaccharidosis VII, Gene Ther. 10: 406.CrossRefPubMedGoogle Scholar
  24. Kornfeld, S., 1986, Trafficking of lysosomal enzymes in normal and disease states, J. Clin. Invest 77: 1.CrossRefPubMedGoogle Scholar
  25. Kosuga, M., Takahashi, S., Sasaki, K., Li, X.K., Fujino, M., Hamada, H., Suzuki, S., Yamada, M., Matsuo, N., and Okuyama, T., 2000, Adenovirus-mediated gene therapy for mucopolysaccharidosis VII: Involvement of cross-correction in wide-spread distribution of the gene products and long-term effects of CTLA-4Ig coexpression, Mol. Ther. 1: 406.CrossRefPubMedGoogle Scholar
  26. Leopold, P.L., Kreitzer, G., Miyazawa, N., Rempel, S., Pfister, K.K., Rodriguez-Boulan, E., and Crystal, R.G., 2000, Dynein- and microtubule-mediated translocation of adenovirus serotype 5 occurs after endosomal lysis, Hum. Gene Ther 11: 151.CrossRefPubMedGoogle Scholar
  27. Li, T. and Davidson, B.L., 1995, Phenotype correction in retinal pigment epithelium in murine mucopolysaccharidosis VII by adenovirus-mediated gene transfer, Proc. Natl. Acad. Sci. USA 92: 7700.CrossRefPubMedGoogle Scholar
  28. Lowenstein, P.R. and Castro, M.G., 2003, Inflammation and adaptive immune responses to adenoviral vectors injected into the brain: Peculiarities, mechanisms, and consequences, Gene Ther. 10: 946.CrossRefPubMedGoogle Scholar
  29. Mach, L., 2002, Biosynthesis of lysosomal proteinases in health and disease, Biol. Chem. 383: 751.CrossRefPubMedGoogle Scholar
  30. Martin-Touaux, E., Puech, J.P., Chateau, D., Emiliani, C., Kremer, E.J., Raben, N., Tancini, B., Orlacchio, A., Kahn, A., and Poenaru, L., 2002, Muscle as a putative producer of acid alpha-glucosidase for glycogenosis type II gene therapy, Hum. Mol. Genet. 11: 1637.CrossRefPubMedGoogle Scholar
  31. Mashhour, B., Couton, D., Perricaudet, M., and Briand, P., 1994, In vivo adenovirus-mediated gene transfer into ocular tissues, Gene Ther. 1: 122.PubMedGoogle Scholar
  32. Meier, O. and Greber, U.F., 2003, Adenovirus endocytosis, J. Gene Med. 5: 451.CrossRefPubMedGoogle Scholar
  33. Nemerow, G.R., 2000, Cell receptors involved in adenovirus entry, Virology 274: 1.CrossRefPubMedGoogle Scholar
  34. Ohashi, T., Watabe, K., Uehara, K., Sly, W.S., Vogler, C., and Eto, Y., 1997, Adenovirus-mediated gene transfer and expression of human beta-glucuronidase gene in the liver, spleen, and central nervous system in mucopolysaccharidosis type VII mice, Proc. Natl. Acad. Sci. USA 94: 1287.CrossRefPubMedGoogle Scholar
  35. Peltola, M., Kyttala, A., Heinonen, O., Rapola, J., Paunio, T., Revah, F., Peltonen, L., and Jalanko, A., 1998, Adenovirus-mediated gene transfer results in decreased lysosomal storage in brain and total correction in liver of aspartylglucosaminuria (AGU) mouse, Gene Ther. 5: 1314.CrossRefPubMedGoogle Scholar
  36. Raper, S.E., Chirmule, N., Lee, F.S., Wivel, N.A., Bagg, A., Gao, G.P., Wilson, J.M., and Batshaw, M.L., 2003, Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer, Mol. Genet. Metab. 80: 148.CrossRefPubMedGoogle Scholar
  37. Scaria, A., St George, J.A., Gregory, R.J., Noelle, R.J., Wadsworth, S.C., Smith, A.E., and Kaplan, J.M., 1997, Antibody to CD40 ligand inhibits both humoral and cellular  immune responses to adenoviral vectors and facilitates repeated administration to mouse airway, Gene Ther. 4: 611.CrossRefPubMedGoogle Scholar
  38. Seshidhar, R.P., Ganesh, S., Limbach, M.P., Brann, T., Pinkstaff, A., Kaloss, M., Kaleko, M., and Connelly, S., 2003, Development of adenovirus serotype 35 as a gene transfer vector, Virology 311: 384.CrossRefGoogle Scholar
  39. Shen, J.S., Meng, X.L., Maeda, H., Ohashi, T., and Eto, Y., 2004, Widespread gene transduction to the central nervous system by adenovirus in utero: implication for prenatal gene therapy to brain involvement of lysosomal storage disease, J. Gene Med. 6: 1206.CrossRefPubMedGoogle Scholar
  40. Shenk, T., 1996, Adenoviridae: The viruses and their replication. In Fields Virology (Eds. B.N. Fields, D.M. Knipe, and P.M. Howley), Philadelphia: Lippincott-Raven, pp. 2111-2148.Google Scholar
  41. Sirena, D., Lilienfeld, B., Eisenhut, M., Kalin, S., Boucke, K., Beerli, R.R., Vogt, L., Ruedl, C., Bachmann, M.F., Greber, U.F., and Hemmi, S., 2004, The human membrane cofactor CD46 is a receptor for species B adenovirus serotype 3, J. Virol. 78: 4454.CrossRefPubMedGoogle Scholar
  42. Sleat, D.E., Lackland, H., Wang, Y., Sohar, I., Xiao, G., Li, H., and Lobel, P., 2005, The human brain mannose 6-phosphate glycoproteome: a complex mixture composed of multiple isoforms of many soluble lysosomal proteins, Proteomics. 5: 1520.CrossRefPubMedGoogle Scholar
  43. Stein, C.S., Ghodsi, A., Derksen, T., and Davidson, B.L., 1999, Systemic and central nervous system correction of lysosomal storage in mucopolysaccharidosis type VII mice, J. Virol. 73: 3424.PubMedGoogle Scholar
  44. Stone, D., Ni, S., Li, Z.Y., Gaggar, A., Di Paolo, N., Feng, Q., Sandig, V., and Lieber, A., 2005, Development and assessment of human adenovirus type 11 as a gene transfer vector, J. Virol. 79: 5090.CrossRefPubMedGoogle Scholar
  45. Trapnell, B.C. and Gorziglia, M., 1994, Gene therapy using adenoviral vectors, Curr. Opin. Biotechnol. 5: 617.CrossRefPubMedGoogle Scholar
  46. Vellodi, A., 2005, Lysosomal storage disorders, Br. J. Haematol. 128: 413.CrossRefPubMedGoogle Scholar
  47. Walkley, S.U., 2001, New proteins from old diseases provide novel insights in cell biology, Curr. Opin. Neurol. 14: 805.CrossRefPubMedGoogle Scholar
  48. Wickham, T.J., 2000, Targeting adenovirus, Gene Ther. 7: 110.CrossRefPubMedGoogle Scholar
  49. Wilson, J.M., 1996, Adenoviruses as gene-delivery vehicles, N. Engl. J. Med. 334: 1185.CrossRefPubMedGoogle Scholar
  50. Xu, F., Ding, E., Liao, S.X., Migone, F., Dai, J., Schneider, A., Serra, D., Chen, Y.T., and Amalfitano, A., 2004, Improved efficacy of gene therapy approaches for Pompe disease using a new, immune-deficient GSD-II mouse model, Gene Ther. 11: 1590.CrossRefPubMedGoogle Scholar
  51. Xu, F., Ding, E., Migone, F., Serra, D., Schneider, A., Chen, Y.T., and Amalfitano, A., 2005, Glycogen storage in multiple muscles of old GSD-II mice can be rapidly cleared after a single intravenous injection with a modified adenoviral vector expressing hGAA, J. Gene Med. 7: 171.CrossRefPubMedGoogle Scholar
  52. Yang, Y., Jooss, K.U., Su, Q., Ertl, H.C., and Wilson, J.M., 1996a, Immune responses to viral antigens versus transgene product in the elimination of recombinant adenovirus-infected hepatocytes in vivo, Gene Ther. 3: 137.Google Scholar
  53. Yang, Y., Nunes, F.A., Berencsi, K., Gonczol, E., Engelhardt, J.F., and Wilson, J.M., 1994, Inactivation of E2a in recombinant adenoviruses improves the prospect for gene therapy in cystic fibrosis, Nat. Genet. 7: 362.CrossRefPubMedGoogle Scholar
  54. Yang, Y., Su, Q., and Wilson, J.M., 1996c, Role of viral antigens in destructive cellular immune responses to adenovirus vector-transduced cells in mouse lungs, J. Virol. 70: 7209.Google Scholar
  55. Yang, Y., Su, Q., Grewal, I.S., Schilz, R., Flavell, R.A., and Wilson, J.M., 1996b, Transient subversion of CD40 ligand function diminishes immune responses to adenovirus vectors in mouse liver and lung tissues, J. Virol. 70: 6370.Google Scholar
  56. Ziegler, R.J., Li, C., Cherry, M., Zhu, Y., Hempel, D., van Rooijen, N., Ioannou, Y.A., Desnick, R.J., Goldberg, M.A., Yew, N.S., and Cheng, S.H., 2002, Correction of the nonlinear dose response improves the viability of adenoviral vectors for gene therapy of Fabry disease, Hum. Gene Ther. 13: 935.CrossRefPubMedGoogle Scholar
  57. Ziegler, R.J., Yew, N.S., Li, C., Cherry, M., Berthelette, P., Romanczuk, H., Ioannou, Y.A., Zeidner, K.M., Desnick, R.J., and Cheng, S.H., 1999, Correction of enzymatic and lysosomal storage defects in Fabry mice by adenovirus-mediated gene transfer, Hum. Gene Ther. 10: 1667.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Dolan Sondhi
    • 1
  • Neil R. Hackett
    • 1
  • Stephen M. Kaminksy
    • 1
  • Ronald G. Crystal
    • 1
  1. 1.Department of Genetic MedicineWeil Medical College of Cornell UniversityNew YorkUSA

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