Gene Therapy

  • Arianna Malgieri
  • Paola Spitalieri
  • Giuseppe Novelli
  • Federica C. Sangiuolo
Part of the Updates in Surgery book series (UPDATESSURG, volume 0)


Technological developments in gene isolation and DNA sequencing have been important factors contributing to the knowledge of the genes associated with numerous diseases. This information has been critical for enhancing our understanding of the genetic basis of disease and the role that specific genes play in human phys


Vascular Endothelial Growth Factor Motor Neuron Spinal Muscular Atroph Human Artificial Chromosome Spinal Muscular Atroph Mouse 
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.


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  1. 1.
    Nathwani AC, Benjamin R, Nienhuis AW, Davidoff AM (2004) Current status and prospects for gene therapy. Vox Sanguinis 87:73–81CrossRefPubMedGoogle Scholar
  2. 2.
    Sangiuolo F, Scaldaferri ML, Filareto A et al (2008) Cftr gene targeting in mouse embryonic stem cells mediated by small fragment homologous replacement (SFHR). Front Biosci 1:2989–2999CrossRefGoogle Scholar
  3. 3.
    Macnab S, Whitehouse A (2009) Progress and prospects: human artificial chromosomes. Gene Ther 16:1180–1188CrossRefPubMedGoogle Scholar
  4. 4.
    De Coppi P, Bartsch G Jr, Siddiqui MM et al (2007) Isolation of amniotic stem cell lines with potential for therapy. Nat Biotechnol 25:100–106CrossRefPubMedGoogle Scholar
  5. 5.
    Spitalieri P, Cortese G, Pietropolli A et al (2009) Identification of multipotent cytotrophoblast cells from human first trimester chorionic villi. Cloning Stem Cells 11:535–556CrossRefPubMedGoogle Scholar
  6. 6.
    Nakayama M (2010) Homologous recombination in human iPS and ES cells for use in gene correction therapy. Drug Discov Today 15:198–202CrossRefPubMedGoogle Scholar
  7. 7.
    Eisenstein M (2010) IPSCs: one cell to rule them all? Nature methods 7:81–85CrossRefGoogle Scholar
  8. 8.
    Rao M, Condic ML (2008) Alternative sources of pluripotent stem cells: scientific solutions to an ethical dilemma. Stem Cells Dev 17:1–10CrossRefPubMedGoogle Scholar
  9. 9.
    Aiuti A, Slavin S, Aker M et al (2002) Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 296:2410–2413CrossRefPubMedGoogle Scholar
  10. 10.
    Gaspar HB, Parsley KL, Howe S et al (2004) Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet 364:2181–2187CrossRefPubMedGoogle Scholar
  11. 11.
    Hacein-Bey-Abina S, Le Deist F, Carlier F et al (2002) Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N Engl J Med 346:1185–1193CrossRefPubMedGoogle Scholar
  12. 12.
    Thrasher A (2007) Severe adverse event in clinical trial of gene therapy for X-SCID. Scholar
  13. 13.
    Kohn DB, Sadelain M, Glorioso JC (2003) Occurrence of leukaemia following gene therapy of X-linked SCID. Nat Rev Cancer 3:477–488CrossRefPubMedGoogle Scholar
  14. 14.
    Aiuti A, Cattaneo F, Galimberti S et al (2009) Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med 360:447–458CrossRefPubMedGoogle Scholar
  15. 15.
    Bainbridge JW, Smith AJ, Barker SS et al (2008) Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med 358:2231–2239CrossRefPubMedGoogle Scholar
  16. 16.
    van Deutekom JC, van Ommen GJ (2003) Advances in Duchenne muscular dystrophy gene therapy. Nat Rev Genet 4:774–783. ReviewCrossRefPubMedGoogle Scholar
  17. 17.
    Cho DH, Tapscott SJ (2007) Myotonic dystrophy: emerging mechanisms for DM1 and DM2. Biochim Biophys Acta 1772:195–204PubMedGoogle Scholar
  18. 18.
    Takeshima Y, Nishio H, Sakamoto H et al (1995) Modulation of in vitro splicing of the upstream intron by modifying an intra-exon sequence which is deleted from the dystrophin gene in dystrophin Kobe. J Clin Invest 95:515–520CrossRefPubMedGoogle Scholar
  19. 19.
    Wu B, Moulton HM, Iversen PL et al (2008) Effective rescue of dystrophin improves cardiac function in dystrophin-deficient mice by a modified morpholino oligomer. Proc Natl Acad Sci USA 105:14814–14819CrossRefPubMedGoogle Scholar
  20. 20.
    Gruenert DC, Bruscia E, Novelli G et al (2003) Sequence specific modification of genomic DNA by small DNA fragments. J Clin Invest 112:637–641PubMedGoogle Scholar
  21. 21.
    Kapsa R, Quigley A, Lynch GS et al (2001) In vivo and in vitro correction of the mdx dystrophin gene nonsense mutation by short-fragment homologous replacement. Hum Gene Ther 12:629–642CrossRefPubMedGoogle Scholar
  22. 22.
    Hoshiya H, Kazuki Y, Abe S et al (2009) A highly stable and nonintegrated human artificial chromosome (HAC) containing the 2.4 Mb entire human dystrophin gene. Molecular Therapy 17:309–317CrossRefPubMedGoogle Scholar
  23. 23.
    Sangiuolo F, Filareto A, Spitalieri P (2005) In vitro restoration of functional SMN protein in human trophoblast cells affected by spinal muscular atrophy by small fragment homologous replacement. Hum Gene Ther 16:869–880CrossRefPubMedGoogle Scholar
  24. 24.
    Monani UR, Sendtner M, Coovert DD et al (2000) The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(−/−) mice and results in a mouse with spinal muscular atrophy. Human Molecular Genetics 9:333–339CrossRefPubMedGoogle Scholar
  25. 25.
    Azzouz M, Le T, Ralph GS et al (2004) Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy. J Clin Invest 114:1726–1731PubMedGoogle Scholar
  26. 26.
    Foust KD, Wang X, McGovern VL (2010) Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol 28:271–274CrossRefPubMedGoogle Scholar
  27. 27.
    Passini MA, Bu J, Roskelley EM et al (2010) CNS-targeted gene therapy improves survival and motor function in a mouse model of spinal muscular atrophy. J Clin Invest 120:1253–1264CrossRefPubMedGoogle Scholar
  28. 28.
    Acsadi G, Anguelov RA, Yang H et al (2002) Increased survival and function of SOD1 mice after glial cell-derived neurotrophic factor gene therapy. Hum Gene Ther 13:1047–1059CrossRefPubMedGoogle Scholar
  29. 29.
    Wang LJ, Lu YY, Muramatsu S et al (2002) Neuroprotective effects of glial cell line-derived neurotrophic factor mediated by an adeno-associated virus vector in a transgenic animal model of amyotrophic lateral sclerosis. J Neurosci 22:6920–6928PubMedGoogle Scholar
  30. 30.
    Azzouz M, Ralph GS, Storkebaum E et al (2004) VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 429:413–417CrossRefPubMedGoogle Scholar
  31. 31.
    Kaspar BK, Lladó J, Sherkat N et al (2003) Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science 301:839–842CrossRefPubMedGoogle Scholar
  32. 32.
    Hsich G, Sena-Esteves M, Breakefield XO (2002) Critical issues in gene therapy for neurologic disease. Hum Gene Ther 13:579–604CrossRefPubMedGoogle Scholar
  33. 33.
    Hacein-Bey-Abina S, Von Kalle C, Schmidt M et al (2003) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302:415–419CrossRefPubMedGoogle Scholar
  34. 34.
    Montini E, Cesana D, Schmidt M et al (2006) Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration. Nat Biotechnol 24:687–696CrossRefPubMedGoogle Scholar
  35. 35.
    Storkebaum E, Lambrechts D, Dewerchin M et al (2005) Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nat Neurosci 8:85–92CrossRefPubMedGoogle Scholar
  36. 36.
    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676CrossRefPubMedGoogle Scholar
  37. 37.
    Gao J, Coggeshall RE, Tarasenko YI, Wu P (2005) Human neural stem cell-derived cholinergic neurons innervate muscle in motoneuron deficient adult rats. Neuroscience 131:257–262CrossRefPubMedGoogle Scholar
  38. 38.
    Xu L, Yan J, Chen D et al (2006) Human neural stem cell grafts ameliorate motor neuron disease in SOD-1 transgenic rats. Transplantation 82:865–875CrossRefPubMedGoogle Scholar
  39. 39.
    Wichterle H, Lieberam I, Porter JA, Jessell TM (2002) Directed differentiation of embryonic stem cells into motor neurons. Cell 110:385–397CrossRefPubMedGoogle Scholar
  40. 40.
    Harper JM, Krishnan C, Darman JS et al (2004) Axonal growth of embryonic stem cell-derived motoneurons in vitro and in motoneuron-injured adult rats. Proc Natl Acad Sci USA 101:7123–7128CrossRefPubMedGoogle Scholar
  41. 41.
    Corti S, Locatelli F, Papadimitriou D et al (2006) Transplanted ALDHhiSSClo neural stem cells generate motor neurons and delay disease progression of nmd mice, an animal model of SMARD1. Hum Mol Genet 15:167–187CrossRefPubMedGoogle Scholar
  42. 42.
    Corti S, Locatelli F, Papadimitriou D et al (2007) Neural stem cells LewisX+ CXCR4+ modify disease progression in an amyotrophic lateral sclerosis model. Brain 130:1289–1305CrossRefPubMedGoogle Scholar
  43. 43.
    Corti S, Nizzardo M, Nardini M (2008) Neural stem cell transplantation can ameliorate the phenotype of a mouse model of spinal muscular atrophy. J Clin Invest 118:3316–3330CrossRefPubMedGoogle Scholar
  44. 44.
    Dimos JT, Rodolfa KT, Niakan KK et al (2008) Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321:1218–1221CrossRefPubMedGoogle Scholar
  45. 45.
    Ebert AD, Yu J, Rose FF et al (2008) Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457:277–280CrossRefPubMedGoogle Scholar
  46. 46.
    Wang KC, Helms JA, Chang HY (2009) Regeneration, repair and remembering identity: the three Rs of Hox gene expression. Trends Cell Biol 19:268–275CrossRefPubMedGoogle Scholar
  47. 47.
    Ghosh AK, Varga J (2007) The transcriptional coactivator and acetyltransferase p300 in fibroblast biology and fibrosis. J Cell Physiol 213:663–671CrossRefPubMedGoogle Scholar
  48. 48.
    Zentilin L, Puligadda U, Lionetti V et al (2009) Cardiomyocyte VEGFR-1 activation by VEGF-B induces compensatory hypertrophy and preserves cardiac function after myocardial infarction. FASEB J 24:1467–1478CrossRefPubMedGoogle Scholar
  49. 49.
    Mulder G, Tallis AJ, Marshall VT et al (2009) Treatment of nonhealing diabetic foot ulcers with a platelet-derived growth factor gene-activated matrix (GAM501): results of a phase 1/2 trial. Wound Repair Regen 17:772–779CrossRefPubMedGoogle Scholar
  50. 50.
    Anitua E, Sánchez M, Orive G et al (2008) Delivering growth factors for therapeutics. Trends Pharmacol Sci 29:37–41CrossRefPubMedGoogle Scholar
  51. 51.
    Tafuro S, Ayuso E, Zacchigna S et al (2009) Inducible adeno-associated virus vectors promote functional angiogenesis in adult organisms via regulated vascular endothelial growth factor expression. Cardiovasc Res 83:663–671CrossRefPubMedGoogle Scholar
  52. 52.
    Voigt K, Izsvák Z, Ivics Z (2008) Targeted gene insertion for molecular medicine. J Mol Med 86:1205–1219CrossRefPubMedGoogle Scholar
  53. 53.
    Tolmachov O (2009) Designing plasmid vectors. Methods Mol Biol 542:117–129CrossRefPubMedGoogle Scholar
  54. 54.
    Smith RH (2008) Adeno-associated virus integration: virus versus vector. Gene Ther 15:817–822CrossRefPubMedGoogle Scholar
  55. 55.
    Rippe B, Rosengren BI, Carlsson O et al (2002) Transendothelial transport: the vesicle controversy. J Vasc Res 39:375–390CrossRefPubMedGoogle Scholar
  56. 56.
    Kulkarni M, Greiser U, O’Brien T et al (2010) Liposomal gene delivery mediated by tissueengineered scaffolds. Trends Biotechnol 28:28–36CrossRefPubMedGoogle Scholar
  57. 57.
    Giacca M (2007) Virus-mediated gene transfer to induce therapeutic angiogenesis: where do we stand? Int J Nanomedicine 2:527–540PubMedGoogle Scholar
  58. 58.
    Ritter T, Lehmann M, Volk HD (2002) Improvements in gene therapy: averting the immune response to adenoviral vectors. Bio Drugs 16:3–10Google Scholar
  59. 59.
    Zentilin L, Giacca M (2008) Adeno-associated virus vectors: versatile tools for in vivo gene transfer. Contrib Nephrol 159:63–77CrossRefPubMedGoogle Scholar
  60. 60.
    Pluta K, Kacprzak MM (2009) Use of HIV as a gene transfer vector. Acta Biochim Pol 56:531–595PubMedGoogle Scholar
  61. 61.
    D’Costa J, Mansfield SG, Humeau LM (2009) Lentiviral vectors in clinical trials: Current status. Curr Opin Mol Ther 11:554–564PubMedGoogle Scholar
  62. 62.
    Mok H, Park JW, Park TG (2007) Micro-encapsulation of PEGylated adenovirus within PLGA microspheres for enhanced stability and gene transfection efficiency. Pharm Res 24:2263–2269CrossRefPubMedGoogle Scholar
  63. 63.
    Enestvedt CK, Hosack L, Winn SR et al (2008) VEGF gene therapy augments localized angiogenesis and promotes anastomotic wound healing: a pilot study in a clinically relevant animal model. J Gastrointest Surg 12:1762–1770CrossRefPubMedGoogle Scholar
  64. 64.
    Trentin D, Hall H, Wechsler S et al (2006) Peptide-matrix-mediated gene transfer of an oxygen-insensitive hypoxia-inducible factor-1alpha variant for local induction of angiogenesis. Proc Natl Acad Sci USA 103:2506–2511CrossRefPubMedGoogle Scholar
  65. 65.
    Cardoso AL, Simões S, de Almeida LP et al (2008) Tf-lipoplexes for neuronal siRNA delivery: a promising system to mediate gene silencing in the CNS. J Control Release 132:113–123CrossRefPubMedGoogle Scholar
  66. 66.
    Mi J, Zhang X, Giangrande PH et al (2005) Targeted inhibition of alphavbeta3 integrin with an RNA aptamer impairs endothelial cell growth and survival. Biochem Biophys Res Commun 338:956–963CrossRefPubMedGoogle Scholar
  67. 67.
    Heyde M, Partridge KA, Oreffo RO et al (2007) Gene therapy used for tissue engineering applications. J Pharm Pharmacol 59:329–350CrossRefPubMedGoogle Scholar
  68. 68.
    Berry CC, Shelton JC, Lee DA (2009) Cell-generated forces influence the viability, metabolism and mechanical properties of fibroblast-seeded collagen gel constructs. J Tissue Eng Regen Med 3:43–53CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Italia 2011

Authors and Affiliations

  • Arianna Malgieri
    • 1
  • Paola Spitalieri
    • 1
  • Giuseppe Novelli
    • 1
  • Federica C. Sangiuolo
    • 1
  1. 1.Department of BiopathologyTor Vergata University of RomeRomeItaly

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