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Hematopoietic Stem Cell Gene Therapy for Lysosomal Storage Disorders: Expected Benefits and Limitations

  • Alessandra BiffiEmail author
  • Ilaria Visigalli
Chapter
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)

Abstract

Gene therapy is recently becoming a therapeutic option for patients affected by LSDs, and new clinical trials are starting worldwide. The state of the development of hematopoietic stem cell gene therapy approaches for LSDs and efforts towards clinical application will be here reviewed.

Keywords

Gene Therapy Hematopoietic Stem Cell Hematopoietic Stem Cell Transplantation Chronic Granulomatous Disease Allogeneic Hematopoietic Stem Cell Transplantation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Sands, M.S., Davidson, B.L.: Gene therapy for lysosomal storage diseases. Mol. Ther. 13, 839–849 (2006)PubMedCrossRefGoogle Scholar
  2. 2.
    Wynn, R.F., Wraith, J.E., Mercer, J., et al.: Improved metabolic correction in patients with lysosomal storage disease treated with hematopoietic stem cell transplant compared with enzyme replacement therapy. J. Pediatr. 154, 609–611 (2009)PubMedCrossRefGoogle Scholar
  3. 3.
    Begley, D.J., Pontikis, C.C., Scarpa, M.: Lysosomal storage diseases and the blood-brain barrier. Curr. Pharm. Des. 14, 1566–1580 (2008)PubMedCrossRefGoogle Scholar
  4. 4.
    Sanai, N., Tramontin, A.D., Quinones-Hinojosa, A., et al.: Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427, 740–744 (2004)PubMedCrossRefGoogle Scholar
  5. 5.
    Orchard, P.J., Tolar, J.: Transplant outcomes in leukodystrophies. Semin. Hematol. 47, 70–78 (2010)PubMedCrossRefGoogle Scholar
  6. 6.
    Biffi, A., Lucchini, G., Rovelli, A., Sessa, M. Metachromatic leukodystrophy: an overview of current and prospective treatments. Bone Marrow Transplant. Suppl 2 (2008).Google Scholar
  7. 7.
    Matzner, U., Schestag, F., Hartmann, D., et al.: Bone marrow stem cell gene therapy of arylsulfatase A-deficient mice, using an arylsulfatase A mutant that is hypersecreted from retrovirally transduced donor-type cells. Hum. Gene Ther. 12, 1021–1033 (2001)PubMedCrossRefGoogle Scholar
  8. 8.
    Matzner, U., Harzer, K., Learish, R.D., Barranger, J.A., Gieselmann, V.: Long-term expression and transfer of arylsulfatase A into brain of arylsulfatase A-deficient mice transplanted with bone marrow expressing the arylsulfatase A cDNA from a retroviral vector. Gene Ther. 7, 1250–1257 (2000)PubMedCrossRefGoogle Scholar
  9. 9.
    Biffi, A., De Palma, M., Quattrini, A., et al.: Correction of metachromatic leukodystrophy in the mouse model by transplantation of genetically modified hematopoietic stem cells. J. Clin. Invest. 113, 1118–1129 (2004)PubMedGoogle Scholar
  10. 10.
    Biffi, A., Capotondo, A., Fasano, S., et al.: Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice. J. Clin. Invest. 116, 3070–3082 (2006)PubMedCrossRefGoogle Scholar
  11. 11.
    Zhou, X.Y., Morreau, H., Rottier, R., et al.: Mouse model for the lysosomal disorder galactosialidosis and correction of the phenotype with overexpressing erythroid precursor cells. Genes Dev. 9, 2623–2634 (1995)PubMedCrossRefGoogle Scholar
  12. 12.
    Zheng, Y., Ryazantsev, S., Ohmi, K., et al.: Retrovirally transduced bone marrow has a therapeutic effect on brain in the mouse model of mucopolysaccharidosis IIIB. Mol. Genet. Metab. 82, 286–295 (2004)PubMedCrossRefGoogle Scholar
  13. 13.
    Eglitis, M.A., Mezey, E.: Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc. Natl. Acad. Sci. U.S.A. 94, 4080–4085 (1997)PubMedCrossRefGoogle Scholar
  14. 14.
    Hoogerbrugge, P.M., Poorthuis, B.J., Romme, A.E., van de Kamp, J.J., Wagemaker, G., van Bekkum, D.W.: Effect of bone marrow transplantation on enzyme levels and clinical course in the neurologically affected twitcher mouse. J. Clin. Invest. 81, 1790–1794 (1988)PubMedCrossRefGoogle Scholar
  15. 15.
    Peters, C., Charnas, L.R., Tan, Y., et al.: Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999. Blood 104, 881–888 (2004)PubMedCrossRefGoogle Scholar
  16. 16.
    Cartier, N., Hacein-Bey-Abina, S., Bartholomae, C.C., et al.: Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 326, 818–823 (2009)PubMedCrossRefGoogle Scholar
  17. 17.
    Priller, J., Flugel, A., Wehner, T., et al.: Targeting gene-modified hematopoietic cells to central nervous system; use of green fluorescent proteine uncovers microglial engraftment. Nat. Med. 7, 1356–1361 (2001)PubMedCrossRefGoogle Scholar
  18. 18.
    Ohmi, K., Greenberg, D.S., Rajavel, K.S., Ryazantsev, S., Li, H.H., Neufeld, E.F.: Activated microglia in cortex of mouse models of mucopolysaccharidoses I and IIIB. Proc. Natl. Acad. Sci. USA. 100, 1902–1907 (2003)PubMedCrossRefGoogle Scholar
  19. 19.
    Wada, R., Tifft, C.J., Proia, R.L.: Microglial activation precedes acute neurodegeneration in Sandhoff disease and is suppressed by bone marrow transplantation. Proc. Natl. Acad. Sci. USA. 97, 10954–10959 (2000)PubMedCrossRefGoogle Scholar
  20. 20.
    Bauer, J., Sminia, T., Wouterlood, F.G., Dijkstra, C.D.: Phagocytic activity of macrophages and microglial cells during the course of acute and chronic relapsing experimental autoimmune encephalomyelitis. J. Neurosci. Res. 38, 365–375 (1994)PubMedCrossRefGoogle Scholar
  21. 21.
    Perry, V.H.: A revised view of the central nervous system microenvironment and major histocompatibility complex class II antigen presentation. J. Neuroimmunol. 90, 113–121 (1998)PubMedCrossRefGoogle Scholar
  22. 22.
    Banati, R.B., Kreutzberg, G.W.: Flow cytometry: measurement of proteolytic and cytotoxic activity of microglia. Clin. Neuropathol. 12, 285–288 (1993)PubMedGoogle Scholar
  23. 23.
    Kaur, C., Hao, A.J., Wu, C.H., Ling, E.A.: Origin of microglia. Microsc. Res. Tech. 54, 2–9 (2001)PubMedCrossRefGoogle Scholar
  24. 24.
    Soulet, D., Rivest, S.: Bone-marrow-derived microglia: myth or reality? Curr. Opin. Pharmacol. 8, 508–518 (2008)PubMedCrossRefGoogle Scholar
  25. 25.
    Ajami, B., Bennett, J.L., Krieger, C., Tetzlaff, W., Rossi, F.M.: Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10, 1538–1543 (2007)PubMedCrossRefGoogle Scholar
  26. 26.
    Mildner, A., Schmidt, H., Nitsche, M., et al.: Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat. Neurosci. 10, 1544–1553 (2007)PubMedCrossRefGoogle Scholar
  27. 27.
    Li, Y., Liu, L., Barger, S.W., Griffin, W.S.: Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J. Neurosci. 23, 1605–1611 (2003)PubMedGoogle Scholar
  28. 28.
    Yeager, A.M., Shinn, C., Shinohara, M., Pardoll, D.M.: Hematopoietic cell transplantation in the twitcher mouse. The effects of pretransplant conditioning with graded doses of busulfan. Transplantation 56, 185–190 (1993)PubMedCrossRefGoogle Scholar
  29. 29.
    Simard, A.R., Soulet, D., Gowing, G., Julien, J.P., Rivest, S.: Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron 49, 489–502 (2006)PubMedCrossRefGoogle Scholar
  30. 30.
    Malm, T.M., Koistinaho, M., Parepalo, M., et al.: Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice. Neurobiol. Dis. 18, 134–142 (2005)PubMedCrossRefGoogle Scholar
  31. 31.
    Ponomarev, E.D., Shriver, L.P., Maresz, K., Dittel, B.N.: Microglial cell activation and proliferation precedes the onset of CNS autoimmunity. J. Neurosci. Res. 81, 374–389 (2005)PubMedCrossRefGoogle Scholar
  32. 32.
    Rodriguez, M., Alvarez-Erviti, L., Blesa, F.J., et al.: Bone-marrow-derived cell differentiation into microglia: a study in a progressive mouse model of Parkinson’s disease. Neurobiol. Dis. 28, 316–325 (2007)PubMedCrossRefGoogle Scholar
  33. 33.
    Wu, Y.P., Matsuda, J., Kubota, A., Suzuki, K., Suzuki, K.: Infiltration of hematogenous lineage cells into the demyelinating central nervous system of twitcher mice. J. Neuropathol. Exp. Neurol. 59, 628–639 (2000)PubMedGoogle Scholar
  34. 34.
    Visigalli, I., Moresco, R.M., Belloli, S., et al.: Monitoring disease evolution and treatment response in lysosomal disorders by the peripheral benzodiazepine receptor ligand PK11195. Neurobiol. Dis. 34, 51–62 (2009)PubMedCrossRefGoogle Scholar
  35. 35.
    Krivit, W., Sung, J.H., Shapiro, E.G., Lockman, L.A.: Microglia: the effector cell for reconstitution of the central nervous system following bone marrow transplantation for lysosomal and peroxisomal storage diseases. Cell Transplant. 4, 385–392 (1995)PubMedCrossRefGoogle Scholar
  36. 36.
    Escolar, M.L., Poe, M.D., Provenzale, J.M., et al.: Transplantation of umbilical-cord blood in babies with infantile Krabbe’s disease. N. Engl. J. Med. 352, 2069–2081 (2005)PubMedCrossRefGoogle Scholar
  37. 37.
    Hacein-Bey-Abina, S., von Kalle, C., Schmidt, M., et al.: A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N. Engl. J. Med. 348, 255–256 (2003)PubMedCrossRefGoogle Scholar
  38. 38.
    Hacein-Bey-Abina, S., Von Kalle, C., Schmidt, M., et al.: LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302, 415–419 (2003)PubMedCrossRefGoogle Scholar
  39. 39.
    Howe, S.J., Mansour, M.R., Schwarzwaelder, K., et al.: Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J. Clin. Invest. 118, 3143–3150 (2008)PubMedCrossRefGoogle Scholar
  40. 40.
    Ott, M.G., Seger, R., Stein, S., Siler, U., Hoelzer, D., Grez, M.: Advances in the treatment of chronic granulomatous disease by gene therapy. Curr. Gene Ther. 7, 155–161 (2007)PubMedCrossRefGoogle Scholar
  41. 41.
    Cattoglio, C., Facchini, G., Sartori, D., et al.: Hot spots of retroviral integration in human CD34+ hematopoietic cells. Blood 110, 1770–1778 (2007)PubMedCrossRefGoogle Scholar
  42. 42.
    Schroder, A.R., Shinn, P., Chen, H., Berry, C., Ecker, J.R., Bushman, F.: HIV-1 integration in the human genome favors active genes and local hotspots. Cell 110, 521–529 (2002)PubMedCrossRefGoogle Scholar
  43. 43.
    Wu, X., Li, Y., Crise, B., Burgess, S.M.: Transcription start regions in the human genome are favored targets for MLV integration. Science 300, 1749–1751 (2003)PubMedCrossRefGoogle Scholar
  44. 44.
    Montini, E., Cesana, D., Schmidt, M., et al.: Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration. Nat. Biotechnol. 24, 687–696 (2006)PubMedCrossRefGoogle Scholar
  45. 45.
    Montini, E., Cesana, D., Schmidt, M., et al.: The genotoxic potential of retroviral vectors is strongly modulated by vector design and integration site selection in a mouse model of HSC gene therapy. J. Clin. Invest. 119, 964–975 (2009)PubMedCrossRefGoogle Scholar
  46. 46.
    Parker Ponder, K., Melniczek, J.R., Xu, L., et al.: Therapeutical neonatal hepatic gene therapy in mucopolisaccharidosis VII dogs. Proc. Natl. Acad. Sci. USA. 99, 13102–13107 (2002)CrossRefGoogle Scholar
  47. 47.
    Mango, R.L., Xu, L., Sands, M.S., et al.: Neonatal retroviral vector-mediated hepatic gene therapy reduces bone, joint, and cartilage disease in mucopolysaccharidosis VII mice and dogs. Mol. Genet. Metab. 82, 4–19 (2004)PubMedCrossRefGoogle Scholar
  48. 48.
    De Geest, B.R., Van Linthout, S.A., Collen, D.: Humoral immune response in mice against a circulating antigen induced by adenoviral transfer is strictly dependent on expression in antigen-presenting cells. Blood 101, 2551–2556 (2003)PubMedCrossRefGoogle Scholar
  49. 49.
    Thomas, C.E., Ehrhardt, A., Kay, M.A.: Progress and problems with the use of viral vectors for gene therapy. Nat. Rev. Genet. 4, 346–358 (2003)PubMedCrossRefGoogle Scholar
  50. 50.
    High, K.: Gene transfer for hemophilia: can therapeutic efficacy in large animals be safely translated to patients? J. Thromb. Haemost. 3, 1682–1691 (2005)PubMedCrossRefGoogle Scholar
  51. 51.
    Brown, B.D., Lillicrap, D.: Dangerous liaisons: the role of “danger” signals in the immune response to gene therapy. Blood 100, 1133–1140 (2002)PubMedCrossRefGoogle Scholar
  52. 52.
    Di Domenico, C., Villani, G.R., Di Napoli, D., et al.: Gene therapy for a mucopolysaccharidosis type I murine model with lentiviral-IDUA vector. Hum. Gene Ther. 16, 81–90 (2005)PubMedCrossRefGoogle Scholar
  53. 53.
    Follenzi, A., Battaglia, M., Lombardo, A., Annoni, A., Roncarolo, M.G., Naldini, L.: Targeting lentiviral vector expression to hepatocytes limits transgene-specific immune response and establishes long-term expression of human antihemophilic factor IX in mice. Blood 103, 3700–3709 (2004)PubMedCrossRefGoogle Scholar
  54. 54.
    Brown, B.D., Venneri, M.A., Zingale, A., Sergi Sergi, L., Naldini, L.: Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transfer. Nat. Med. 12, 585–591 (2006)PubMedCrossRefGoogle Scholar
  55. 55.
    Spencer, B.J., Verma, I.M.: Targeted delivery of proteins across the blood-brain barrier. Proc. Natl. Acad. Sci. USA. 104, 7594–7599 (2007)PubMedCrossRefGoogle Scholar
  56. 56.
    Young, P.P., Fantz, C.R., Sands, M.S.: VEGF disrupts the neonatal blood-brain barrier and increases life span after non-ablative BMT in a murine model of congenital neurodegeneration caused by a lysosomal enzyme deficiency. Exp. Neurol. 188, 104–114 (2004)PubMedCrossRefGoogle Scholar
  57. 57.
    Naldini, L., Blomer, U., Gallay, P., et al.: In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272, 263–267 (1996)PubMedCrossRefGoogle Scholar
  58. 58.
    Zufferey, R., Nagy, D., Mandel, R.J., Naldini, L., Trono, D.: Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo. Nat. Biotechnol. 15, 871–875 (1997)PubMedCrossRefGoogle Scholar
  59. 59.
    Zufferey, R., Dull, T., Mandel, R.J., et al.: Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J. Virol. 72, 9873–9880 (1998)PubMedGoogle Scholar
  60. 60.
    Blomer, U., Naldini, L., Kafri, T., Trono, D., Verma, I.M., Gage, F.H.: Highly efficient and sustained gene transfer in adult neurons with a lentivirus vector. J. Virol. 71, 6641–6649 (1997)PubMedGoogle Scholar
  61. 61.
    Kordower, J.H., Bloch, J., Ma, S.Y., et al.: Lentiviral gene transfer to the nonhuman primate brain. Exp. Neurol. 160, 1–16 (1999)PubMedCrossRefGoogle Scholar
  62. 62.
    Taymans, J.M., Van den Haute, C., Baekelandt, V.: Distribution of PINK1 and LRRK2 in rat and mouse brain. J. Neurochem. 98, 951–961 (2006)PubMedCrossRefGoogle Scholar
  63. 63.
    Burger, C., Nash, K., Mandel, R.J.: Recombinant adeno-associated viral vectors in the nervous system. Hum. Gene Ther. 16, 781–791 (2005)PubMedCrossRefGoogle Scholar
  64. 64.
    Tenenbaum, L., Chtarto, A., Lehtonen, E., Velu, T., Brotchi, J., Levivier, M.: Recombinant AAV-mediated gene delivery to the central nervous system. J. Gene Med. 6(suppl 1), S212–S222 (2004)PubMedCrossRefGoogle Scholar
  65. 65.
    Consiglio, A., Quattrini, A., Martino, S., et al.: In vivo gene therapy of metachromatic leukodystrophy by lentiviral vectors: correction of neuropathology and protection against learning impairment in affected mice. Nat. Med. 7, 310–316 (2001)PubMedCrossRefGoogle Scholar
  66. 66.
    Desmaris, N., Verot, L., Puech, J.P., Caillaud, C., Vanier, M.T., Heard, J.M.: Prevention of neuropathology in the mouse model of Hurler syndrome. Ann. Neurol. 56, 68–76 (2004)PubMedCrossRefGoogle Scholar
  67. 67.
    Ciron, C., Desmaris, N., Colle, M.A., et al.: Gene therapy of the brain in the dog model of Hurler’s syndrome. Ann. Neurol. 60, 204–213 (2006)PubMedCrossRefGoogle Scholar
  68. 68.
    Passini, M.A., Dodge, J.C., Bu, J., et al.: Intracranial delivery of CLN2 reduces brain pathology in a mouse model of classical late infantile neuronal ceroid lipofuscinosis. J. Neurosci. 26, 1334–1342 (2006)PubMedCrossRefGoogle Scholar
  69. 69.
    Cabrera-Salazar, M.A., Roskelley, E.M., Bu, J., et al.: Timing of therapeutic intervention determines functional and survival outcomes in a mouse model of late infantile batten disease. Mol. Ther. 15, 1782–1788 (2007)PubMedCrossRefGoogle Scholar
  70. 70.
    Crystal, R.G., Sondhi, D., Hackett, N.R., et al.: Clinical protocol. Administration of a replication-deficient adeno-associated virus gene transfer vector expressing the human CLN2 cDNA to the brain of children with late infantile neuronal ceroid lipofuscinosis. Hum. Gene Ther. 15, 1131–1154 (2004)PubMedGoogle Scholar
  71. 71.
    Janson, C., McPhee, S., Bilaniuk, L., et al.: 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 (2002)PubMedCrossRefGoogle Scholar
  72. 72.
    Worgall, S., Sondhi, D., Hackett, N.R., et al.: Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA. Hum. Gene Ther. 19, 463–474 (2008)PubMedCrossRefGoogle Scholar
  73. 73.
    Im, D.S., Heise, C.E., Nguyen, T., O’Dowd, B.F., Lynch, K.R.: Identification of a molecular target of psychosine and its role in globoid cell formation. J. Cell Biol. 153, 429–434 (2001)PubMedCrossRefGoogle Scholar
  74. 74.
    Jesionek-Kupnicka, D., Majchrowska, A., Krawczyk, J., et al.: Krabbe disease: an ultrastructural study of globoid cells and reactive astrocytes at the brain and optic nerves. Folia Neuropathol. 35, 155–162 (1997)PubMedGoogle Scholar
  75. 75.
    Giri, S., Khan, M., Rattan, R., Singh, I., Singh, A.K.: Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death. J. Lipid Res. 47, 1478–1492 (2006)PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine and Stem CellsSan Raffaele Scientific InstituteMilanItaly

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