Pediatric Nephrology

, Volume 20, Issue 2, pp 118–124

A realistic chance for gene therapy in the near future

Editorial Commentary

Abstract

The expanding knowledge of the genetic and cellular mechanisms of human diseases in the post-genomic era coupled with the development of different vector systems to efficiently transfer genes to a variety of cell types and organs in vivo gave rise to the concept of gene therapy as a promising therapeutic option for genetic and acquired diseases. Gene therapy has been the focus of both enthusiasm and critique in the past years. Major progress has been achieved in evaluating gene therapy in clinical trials. However, a number of hurdles must still be overcome to make gene therapy safe and applicable for human diseases. Increased knowledge of the interaction of the gene therapy vehicles with the host has resulted in modifications of existing and the development of new vector systems, as well as adjustments of future clinical applications. Adeno-associated virus vectors, retrovirus- and lentivirus-based vectors show great promise for the correction of monogenic diseases. Correction of the genetic defect can be attempted by either in vivo administration to directly target a diseased organ or by administration of ex vivo genetically modified cells, e.g., bone marrow stem cells. The lack of persistent expression and the immune responses of the host have limited the use of adenovirus vectors for the permanent correction of monogenic diseases. However, the ease of production and the number of cell types and organs that can be efficiently infected make adenovirus-based vectors a promising tool for applications where permanent gene expression is not the therapeutic goal or where the induction of immune responses is the desired response, as for genetic vaccines. Overall, gene therapy remains promising for the correction of genetic as well as acquired disorders, where permanent or transient expression of a gene product will be therapeutic.

Keywords

Gene therapy Gene transfer vectors Clinical trials 

References

  1. 1.
    Anderson WF (1998) Human gene therapy. Nature 392:25–30CrossRefGoogle Scholar
  2. 2.
    Mulligan RC (1993) The basic science of gene therapy. Science 260:926–932PubMedGoogle Scholar
  3. 3.
    Crystal RG (1995) Transfer of genes to humans: early lessons and obstacles to success. Science 270:404–410PubMedGoogle Scholar
  4. 4.
    Driskell RA, Engelhardt JF (2003) Current status of gene therapy for inherited lung diseases. Annu Rev Physiol 65:585−612CrossRefPubMedGoogle Scholar
  5. 5.
    Thomas CE, Ehrhardt A, Kay MA (2003) Progress and problems with the use of viral vectors for gene therapy. Nat Rev Genet 4:346−358CrossRefPubMedGoogle Scholar
  6. 6.
    Hacein-Bey-Abina S, Kalle C von, Schmidt M, Le Deist F, Wulffraat N, McIntyre E, Radford I, Villeval JL, Fraser CC, Cavazzana-Calvo M, Fischer A (2003) A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 348:255–256CrossRefPubMedGoogle Scholar
  7. 7.
    Raper SE, Chirmule N, Lee FS, Wivel NA, Bagg A, Gao GP, Wilson JM, Batshaw ML (2003) Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab 80:148–158CrossRefPubMedGoogle Scholar
  8. 8.
    Hackett NR, Kaminsky SM, Sondhi D, Crystal RG (2000) Antivector and antitransgene host responses in gene therapy. Curr Opin Mol Ther 2:376–382PubMedGoogle Scholar
  9. 9.
    Hacein-Bey-Abina S, Kalle C von, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, Lim A, Osborne CS, Pawliuk R, Morillon E, Sorensen R, Forster A, Fraser P, Cohen JI, de Saint BG, Alexander I, Wintergerst U, Frebourg T, Aurias A, Stoppa-Lyonnet D, Romana S, Radford-Weiss I, Gross F, Valensi F, Delabesse E, Macintyre E, Sigaux F, Soulier J, Leiva LE, Wissler M, Prinz C, Rabbitts TH, Le Deist F, Fischer A, Cavazzana-Calvo M (2003) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302:415–419CrossRefPubMedGoogle Scholar
  10. 10.
    McCormack MP, Rabbitts TH (2004) Activation of the T-cell oncogene LMO2 after gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 350:913–922CrossRefPubMedGoogle Scholar
  11. 11.
    Imai E, Takabatake Y, Mizui M, Isaka Y (2004) Gene therapy in renal diseases. Kidney Int 65:1551–1555CrossRefPubMedGoogle Scholar
  12. 12.
    Hanss B, Bruggeman LA (2003) Applications of gene therapy to kidney disease. Curr Opin Nephrol Hypertens 12:439–445CrossRefPubMedGoogle Scholar
  13. 13.
    Lien YH, Lai LW (2003) Renal gene transfer: nonviral approaches. Mol Biotechnol 24:283–294CrossRefPubMedGoogle Scholar
  14. 14.
    Lipkowitz MS, Klotman ME, Bruggeman LA, Nicklin P, Hanss B, Rappaport J, Klotman PE (1996) Molecular therapy for renal diseases. Am J Kidney Dis 28:475–492PubMedGoogle Scholar
  15. 15.
    Alton EW, Middleton PG, Caplen NJ, Smith SN, Steel DM, Munkonge FM, Jeffery PK, Geddes DM, Hart SL, Williamson R (1993) Non-invasive liposome-mediated gene delivery can correct the ion transport defect in cystic fibrosis mutant mice. Nat Genet 5:135–142CrossRefPubMedGoogle Scholar
  16. 16.
    Lee ER, Marshall J, Siegel CS, Jiang C, Yew NS, Nichols MR, Nietupski JB, Ziegler RJ, Lane MB, Wang KX, Wan NC, Scheule RK, Harris DJ, Smith AE, Cheng SH (1996) Detailed analysis of structures and formulations of cationic lipids for efficient gene transfer to the lung. Hum Gene Ther 7:1701–1717PubMedGoogle Scholar
  17. 17.
    Sandrin V, Russell SJ, Cosset FL (2003) Targeting retroviral and lentiviral vectors. Curr Top Microbiol Immunol 281:137–178PubMedGoogle Scholar
  18. 18.
    Burton EA, Fink DJ, Glorioso JC (2002) Gene delivery using herpes simplex virus vectors. DNA Cell Biol 21:915–936CrossRefPubMedGoogle Scholar
  19. 19.
    Shenk T (1996) Adenoviridae: the viruses and their replication. In: Fields BN, Knipe DM, Howley PM (eds) Fields virology. Lippincott-Raven, Philadelphia, pp 2111–2148Google Scholar
  20. 20.
    Hackett NR, Crystal RG (2000) Adenovirus vectors for gene therapy. In: Lasic D, Templeton NS (eds) Gene therapy: therapeutic mechanisms and strategies. Dekker, New York, pp 17–40Google Scholar
  21. 21.
    Crystal RG, McElvaney NG, Rosenfeld MA, Chu CS, Mastrangeli A, Hay JG, Brody SL, Jaffe HA, Eissa NT, Danel C (1994) Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis. Nat Genet 8:42–51CrossRefPubMedGoogle Scholar
  22. 22.
    Christ M, Lusky M, Stoeckel F, Dreyer D, Dieterle A, Michou AI, Pavirani A, Mehtali M (1997) Gene therapy with recombinant adenovirus vectors: evaluation of the host immune response. Immunol Lett 57:19–25CrossRefPubMedGoogle Scholar
  23. 23.
    Raper SE, Yudkoff M, Chirmule N, Gao GP, Nunes F, Haskal ZJ, Furth EE, Propert KJ, Robinson MB, Magosin S, Simoes H, Speicher L, Hughes J, Tazelaar J, Wivel NA, Wilson JM, Batshaw ML (2002) A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency. Hum Gene Ther 13:163–175CrossRefPubMedGoogle Scholar
  24. 24.
    Rainov NG, Ren H (2003) Gene therapy for human malignant brain tumors. Cancer J 9:180–188PubMedGoogle Scholar
  25. 25.
    Shinoura N, Hamada H (2003) Gene therapy using an adenovirus vector for apoptosis-related genes is a highly effective therapeutic modality for killing glioma cells. Curr Gene Ther 3:147–153PubMedGoogle Scholar
  26. 26.
    Wildner O (2003) Comparison of replication-selective, oncolytic viruses for the treatment of human cancers. Curr Opin Mol Ther 5:351–361PubMedGoogle Scholar
  27. 27.
    Rosengart TK, Lee LY, Patel SR, Sanborn TA, Parikh M, Bergman GW, Hachamovitch R, Szulc M, Kligfield PD, Okin PM, Hahn RT, Devereux RB, Post MR, Hackett NR, Foster T, Grasso TM, Lesser ML, Isom OW, Crystal RG (1999) Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe coronary artery disease. Circulation 100:468–474PubMedGoogle Scholar
  28. 28.
    Khan TA, Sellke FW, Laham RJ (2003) Gene therapy progress and prospects: therapeutic angiogenesis for limb and myocardial ischemia. Gene Ther 10:285–291CrossRefPubMedGoogle Scholar
  29. 29.
    Xiang ZQ, Yang Y, Wilson JM, Ertl HC (1996) A replication-defective human adenovirus recombinant serves as a highly efficacious vaccine carrier. Virology 219:220–227CrossRefPubMedGoogle Scholar
  30. 30.
    Shiver JW, Emini EA (2004) Recent advances in the development of HIV-1 vaccines using replication-incompetent adenovirus vectors. Annu Rev Med 55:355–372CrossRefPubMedGoogle Scholar
  31. 31.
    Sullivan NJ, Geisbert TW, Geisbert JB, Xu L, Yang ZY, Roederer M, Koup RA, Jahrling PB, Nabel GJ (2003) Accelerated vaccination for Ebola virus haemorrhagic fever in non-human primates. Nature 424:681–684CrossRefPubMedGoogle Scholar
  32. 32.
    Worgall S, Busch A, Rivara M, Bonnyay D, Leopold PL, Merritt R, Hackett NR, Rovelink PW, Bruder JT, Wickham TJ, Kovesdi I, Crystal RG (2004) Modification to the capsid of the adenovirus vector that enhances dendritic cell infection and transgene-specific cellular immune responses. J Virol 78:2572–2580CrossRefPubMedGoogle Scholar
  33. 33.
    Kochanek S, Schiedner G, Volpers C (2001) High-capacity ‘gutless’ adenoviral vectors. Curr Opin Mol Ther 3:454–463PubMedGoogle Scholar
  34. 34.
    Schiedner G, Morral N, Parks RJ, Wu Y, Koopmans SC, Langston C, Graham FL, Beaudet AL, Kochanek S (1998) Genomic DNA transfer with a high-capacity adenovirus vector results in improved in vivo gene expression and decreased toxicity. Nat Genet 18:180–183CrossRefPubMedGoogle Scholar
  35. 35.
    Linden RM, Berns KI (2000) Molecular biology of adeno-associated viruses. Contrib Microbiol 4:68–84PubMedGoogle Scholar
  36. 36.
    Grimm D, Kay MA (2003) From virus evolution to vector revolution: use of naturally occurring serotypes of adeno-associated virus (AAV) as novel vectors for human gene therapy. Curr Gene Ther 3:281–304PubMedGoogle Scholar
  37. 37.
    Gao G, Alvira MR, Somanathan S, Lu Y, Vandenberghe LH, Rux JJ, Calcedo R, Sanmiguel J, Abbas Z, Wilson JM (2003) Adeno-associated viruses undergo substantial evolution in primates during natural infections. Proc Natl Acad Sci U S A 100:6081–6086CrossRefPubMedGoogle Scholar
  38. 38.
    Couto LB, Pierce GF (2003) AAV-mediated gene therapy for hemophilia. Curr Opin Mol Ther 5:517–523PubMedGoogle Scholar
  39. 39.
    Buning H, Nicklin SA, Perabo L, Hallek M, Baker AH (2003) AAV-based gene transfer. Curr Opin Mol Ther 5:367–375PubMedGoogle Scholar
  40. 40.
    Janson C, McPhee S, Bilaniuk L, Haselgrove J, Testaiuti M, Freese A, Wang DJ, Shera D, Hurh P, Rupin J, Saslow E, Goldfarb O, Goldberg M, Larijani G, Sharrar W, Liouterman L, Camp A, Kolodny E, Samulski J, Leone P (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 13:1391–1412CrossRefPubMedGoogle Scholar
  41. 41.
    Kaplitt MG, Leone P, Samulski RJ, Xiao X, Pfaff DW, O’Malley KL, During MJ (1994) Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain. Nat Genet 8:148–154CrossRefPubMedGoogle Scholar
  42. 42.
    Herzog RW (2004) AAV-mediated gene transfer to skeletal muscle. Methods Mol Biol 246:179–194PubMedGoogle Scholar
  43. 43.
    Aiuti A, Slavin S, Aker M, Ficara F, Deola S, Mortellaro A, Morecki S, Andolfi G, Tabucchi A, Carlucci F, Marinello E, Cattaneo F, Vai S, Servida P, Miniero R, Roncarolo MG, Bordignon C (2002) Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 296:2410–2413CrossRefPubMedGoogle Scholar
  44. 44.
    Cavazzana-Calvo M, Hacein-Bey S, Saint BG de, Gross F, Yvon E, Nusbaum P, Selz F, Hue C, Certain S, Casanova JL, Bousso P, Deist FL, Fischer A (2000) Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 288:669–672CrossRefPubMedGoogle Scholar
  45. 45.
    Kafri T (2004) Gene delivery by lentivirus vectors. An overview. Methods Mol Biol 246:367–390PubMedGoogle Scholar
  46. 46.
    Rivella S, Sadelain M (2002) Therapeutic globin gene delivery using lentiviral vectors. Curr Opin Mol Ther 4:505–514PubMedGoogle Scholar
  47. 47.
    Bushman FD (2003) Targeting survival: integration site selection by retroviruses and LTR-retrotransposons. Cell 115:135–138CrossRefPubMedGoogle Scholar
  48. 48.
    Recillas-Targa F, Valadez-Graham V, Farrell CM (2004) Prospects and implications of using chromatin insulators in gene therapy and transgenesis. Bioessays 26:796–807CrossRefPubMedGoogle Scholar
  49. 49.
    Wu X, Li Y, Crise B, Burgess SM (2003) Transcription start regions in the human genome are favored targets for MLV integration. Science 300:1749–1751CrossRefPubMedGoogle Scholar
  50. 50.
    Bowers WJ, Olschowka JA, Federoff HJ (2003) Immune responses to replication-defective HSV-1 type vectors within the CNS: implications for gene therapy. Gene Ther 10:941–945CrossRefPubMedGoogle Scholar
  51. 51.
    Marshall E (1999) Gene therapy death prompts review of adenovirus vector. Science 286:2244–2245CrossRefPubMedGoogle Scholar
  52. 52.
    Harvey BG, Maroni J, O’Donoghue KA, Chu KW, Muscat JC, Pippo AL, Wright CE, Hollmann C, Wisnivesky JP, Kessler PD, Rasmussen HS, Rosengart TK, Crystal RG (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 13:15–63CrossRefPubMedGoogle Scholar
  53. 53.
    Zhang YC, Powers M, Wasserfall C, Brusko T, Song S, Flotte T, Snyder RO, Potter M, Scott-Jorgensen M, Campbell-Thompson M, Crawford JM, Nick HS, Agarwal A, Ellis TM, Atkinson MA (2004) Immunity to adeno-associated virus serotype 2 delivered transgenes imparted by genetic predisposition to autoimmunity. Gene Ther 11:233–240CrossRefPubMedGoogle Scholar
  54. 54.
    Flotte TR, Brantly ML, Spencer LT, Byrne BJ, Spencer CT, Baker DJ, Humphries M (2004) Phase I trial of intramuscular injection of a recombinant adeno-associated virus alpha 1-antitrypsin (rAAV2-CB-hAAT) gene vector to AAT-deficient adults. Hum Gene Ther 15:93–128CrossRefPubMedGoogle Scholar
  55. 55.
    Manno CS, Chew AJ, Hutchison S, Larson PJ, Herzog RW, Arruda VR, Tai SJ, Ragni MV, Thompson A, Ozelo M, Couto LB, Leonard DG, Johnson FA, McClelland A, Scallan C, Skarsgard E, Flake AW, Kay MA, High KA, Glader B (2003) AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood 101:2963–2972CrossRefPubMedGoogle Scholar
  56. 56.
    High KA (2004) Clinical gene transfer studies for hemophilia B. Semin Thromb Hemost 30:257–267CrossRefPubMedGoogle Scholar
  57. 57.
    Mount JD, Herzog RW, Tillson DM, Goodman SA, Robinson N, McCleland ML, Bellinger D, Nichols TC, Arruda VR, Lothrop CD Jr, High KA (2002) Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy. Blood 99:2670–2676CrossRefPubMedGoogle Scholar
  58. 58.
    Herzog RW, Mount JD, Arruda VR, High KA, Lothrop CD Jr (2001) Muscle-directed gene transfer and transient immune suppression result in sustained partial correction of canine hemophilia B caused by a null mutation. Mol Ther 4:192–200CrossRefPubMedGoogle Scholar
  59. 59.
    Lipkowitz MS, Hanss B, Tulchin N, Wilson PD, Langer JC, Ross MD, Kurtzman GJ, Klotman PE, Klotman ME (1999) Transduction of renal cells in vitro and in vivo by adeno-associated virus gene therapy vectors. J Am Soc Nephrol 10:1908–1915PubMedGoogle Scholar
  60. 60.
    Miyazaki Y, Oshima K, Fogo A, Ichikawa I (2003) Evidence that bone morphogenetic protein 4 has multiple biological functions during kidney and urinary tract development. Kidney Int 63:835–844CrossRefPubMedGoogle Scholar
  61. 61.
    Yamagishi H, Yokoo T, Imasawa T, Mitarai T, Kawamura T, Utsunomiya Y (2001) Genetically modified bone marrow-derived vehicle cells site specifically deliver an anti-inflammatory cytokine to inflamed interstitium of obstructive nephropathy. J Immunol 166:609–616PubMedGoogle Scholar
  62. 62.
    Yokoo T, Ohashi T, Utsunomiya Y, Okamoto A, Suzuki T, Shen JS, Tanaka T, Kawamura T, Hosoya T (2003) Gene delivery using human cord blood-derived CD34+cells into inflamed glomeruli in NOD/SCID mice. Kidney Int 64:102–109CrossRefPubMedGoogle Scholar
  63. 63.
    Forbes SJ, Poulsom R, Wright NA (2002) Hepatic and renal differentiation from blood-borne stem cells. Gene Ther 9:625–630CrossRefPubMedGoogle Scholar
  64. 64.
    Rafii S, Heissig B, Hattori K (2002) Efficient mobilization and recruitment of marrow-derived endothelial and hematopoietic stem cells by adenoviral vectors expressing angiogenic factors. Gene Ther 9:631–641CrossRefPubMedGoogle Scholar
  65. 65.
    Poulsom R, Alison MR, Cook T, Jeffery R, Ryan E, Forbes SJ, Hunt T, Wyles S, Wright NA (2003) Bone marrow stem cells contribute to healing of the kidney. J Am Soc Nephrol 14 [Suppl 1]: S48–S54Google Scholar
  66. 66.
    Isaka Y, Akagi Y, Ando Y, Tsujie M, Sudo T, Ohno N, Border WA, Noble NA, Kaneda Y, Hori M, Imai E (1999) Gene therapy by transforming growth factor-beta receptor-IgG Fc chimera suppressed extracellular matrix accumulation in experimental glomerulonephritis. Kidney Int 55:465–475CrossRefPubMedGoogle Scholar
  67. 67.
    Swenson KM, Ke B, Wang T, Markowitz JS, Maggard MA, Spear GS, Imagawa DK, Goss JA, Busuttil RW, Seu P (1998) Fas ligand gene transfer to renal allografts in rats: effects on allograft survival. Transplantation 65:155–160PubMedGoogle Scholar
  68. 68.
    Tomasoni S, Azzollini N, Casiraghi F, Capogrossi MC, Remuzzi G, Benigni A (2000) CTLA4Ig gene transfer prolongs survival and induces donor-specific tolerance in a rat renal allograft. J Am Soc Nephrol 11:747–752PubMedGoogle Scholar
  69. 69.
    Tomasoni S, Longaretti L, Azzollini N, Gagliardini E, Mister M, Buehler T, Remuzzi G, Benigni A (2004) Favorable effect of cotransfection with TGF-beta and CTLA4Ig of the donor kidney on allograft survival. Am J Nephrol 24:275–283CrossRefPubMedGoogle Scholar

Copyright information

© IPNA 2004

Authors and Affiliations

  1. 1.Department of Pediatrics and Genetic MedicineWeill Medical College of Cornell UniversityNew YorkUSA

Personalised recommendations