Somatic Gene Therapy, Paradigm Shift or Pandora’s Box

A perspective on gene therapy
  • Mark Lawler

Abstract

Gene therapy may be defined as the introduction of genetic material into the cells of a patient in an effort to help cure the disease either by producing a gene product which is missing or in reduced amounts in the patient due to a genetic mutation in the individual (eg Factor VIII protein for haemophilia) or by introduction of new genetic material which either directly or indirectly will help to combat the disease (eg genetic vaccination). Therapeutic genes are delivered using a carrier (called a vector) which may be a non functional viral vector or by using non viral vector approaches such as liposomes or other carrier molecules. All gene therapy protocols involve the introduction of genetic material into cells that have a finite life span such as blood cells, liver cells etc (termed somatic tissue), thus the introduced gene is not passed on to the next generation. This type of gene therapy is known as somatic gene therapy and is in contrast to the concept of germ line gene therapy (which would involve a gene being introduced into sperm or ova so that the gene could be inherited by the children of the patient). Germ line gene therapy is subject to an international moratorium.

Keywords

Cholesterol Europe Dopamine Recombination Adenosine 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Parkman R, Weinberg K, Crooks G, Nolta J, Kapoor N, Kohn D, Gene therapy for adenosine deaminase deficiency. Annu Rev Med. 2000;51:33–47PubMedCrossRefGoogle Scholar
  2. 2.
    Zeitlin PL Cystic fibrosis gene therapy trials and tribulations. Mol Ther. 2000;l(l):5–6.CrossRefGoogle Scholar
  3. 3.
    Alton E, Geddes D Cystic fibrosis clinical trials. Adv Drug Deliv Rev. 1998 2;30(l–3):205–217.Google Scholar
  4. 4.
    Mann MJ Gene therapy for peripheral arterial disease. Mol Med Today. 2000;6(7):285–91.PubMedCrossRefGoogle Scholar
  5. 5.
    Raizada MK, Francis SC, Wang H, Gelband CH, Reaves PY, Katovich MJ. Targeting of the renin-angiotensin system by antisense gene therapy: a possible strategy for the long-term control of hypertension. Hypertens. 2000 Apr;18(4):353–62.Google Scholar
  6. 6.
    Stedman H, Wilson JM, Finke R, Kleckner AL, Mendell J Phase I clinical trial utilizing gene therapy for limb girdle muscular dystrophy: alpha-, beta-, gamma-, or delta-sarcoglycan gene delivered with intramuscular instillations of adeno-associated vectors. Hum Gene Ther. 2000 20;11(5):777–90.Google Scholar
  7. 7.
    Bjorklund A The use of neural stem cells for gene therapy in the central nervous system. Gene Med. 1999;l(3):223–6Google Scholar
  8. 8.
    Latchman DS. Herpes virus vectors for gene therapy in the nervous system. Biochem Soc Trans. 1999;27(6):847–51PubMedGoogle Scholar
  9. 9.
    Costello E, Munoz M, Buetti E, Meylan PR, Diggelmann H, Thali M. Gene transfer into stimulated and unstimulated T lymphocytes by HIV-1-derived lentiviral vectors. Gene Ther. 2000 7(7):596–604PubMedCrossRefGoogle Scholar
  10. 10.
    Stein CS, Martins I, Davidson BL Long-term reversal of hypercholesterolemia in low density lipoprotein receptor (LDLR)-deficient mice by adenovirus-mediated LDLR gene transfer combined with CD 154 blockade. J Gene Med. 2000;2(1):41–51PubMedCrossRefGoogle Scholar
  11. 11.
    Restifo NP, Ying H, Hwang L, Leitner WW. The promise of nucleic acid vaccines. Gene Ther. 2000 ;7:89–92.PubMedCrossRefGoogle Scholar
  12. 12.
    Thompson AR. Gene therapy for the haemophilias. Haemophilia. 2000;6 Suppl 1:115–9PubMedCrossRefGoogle Scholar
  13. 13.
    Ohashi T, Yokoo T, Iizuka S, Kobayashi H, Sly WS, Eto Y. Reduction of lysosomal storage in murine mucopolysaccharidosis type VII by transplantation of normal and genetically modified macrophages. Blood. 2000;95(11):3631–3PubMedGoogle Scholar
  14. 14.
    Rosenberg SA, Aebersold P, Cornetta K, Kasid A, Morgan RA, Moen R, Karson EM, Lotze MT, Yang JC, Topalian SL, et al Gene transfer into humans-immunotherapy of patients with advanced melanoma, using tumour-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med. 1990;323(9):570–8PubMedCrossRefGoogle Scholar
  15. 15.
    Rosenberg SA. Immunotherapy and gene therapy of cancer. Cancer Res. 1991,51(18 Suppl):5074s–5079PubMedGoogle Scholar
  16. 16.
    Blaese RM, Culver KW, Chang L, Anderson WF, Mullen C, Nienhuis A, Carter C, Dunbar C, Leitman S, Berger M, et al. Treatment of severe combined immunodeficiency disease (SCID) due to adenosine deaminase deficiency with CD34+ selected autologous peripheral blood cells transduced with a human ADA gene. Amendment to clinical research project, Project 90-C-195, January 10, 1992. Hum Gene Ther. 1993;4(4):521–7PubMedCrossRefGoogle Scholar
  17. 17.
    Bordignon C, Notarangelo LD, Nobili N, Ferrari G, Casorati G, Panina P, Mazzolari E, Maggioni D, Rossi C, Servida P, et al. Gene therapy in peripheral blood lymphocytes and bone marrow for ADA- immunodeficient patients. Science. 1995;270(5235):470–5PubMedCrossRefGoogle Scholar
  18. 18.
    Anderson WF. Human gene therapy. Nature. 1998,392(6679 Suppl):25–30PubMedGoogle Scholar
  19. 19.
    Barranger JA, Rice EO, Swaney WP Gene transfer approaches to the lysosomal storage disorders. Neurochem Res. 1999;24(4):601–15PubMedCrossRefGoogle Scholar
  20. 20.
    Sferra TJ, Qu G, McNeely D, Rennard R, Clark KR, Lo WD, Johnson PR Recombinant adeno-associated virus-mediated correction of lysosomal storage within the central nervous system of the adult mucopolysaccharidosis type VII mouse. Hum Gene Ther. 2000Mar;ll(4):507–19CrossRefGoogle Scholar
  21. 21.
    Wang L, Nichols TC, Read MS, Bellinger DA, Verma IM. Sustained expression of therapeutic level of factor IX in hemophilia B dogs by AAV-mediated gene therapy in liver. Mol Ther. 2000,1(2): 54–8CrossRefGoogle Scholar
  22. 22.
    Zuckerman JB, Robinson CB, McCoy KS, Shell R, Sferra TJ, Chirmule N, Magosin SA, Propert KJ, Brown-Parr EC, Hughes JV, Tazelaar J, Baker C, Goldman MJ, Wilson JM. A phase I study of adenovirus-mediated transfer of the human cystic fibrosis transmembrane conductance regulator gene to a lung segment of individuals with cystic fibrosis. Hum Gene Ther. 1999;10(18):2973–85PubMedCrossRefGoogle Scholar
  23. 23.
    Blesch A, Grill RJ, Tuszynski MH Neurotrophin gene therapy in CNS models of trauma and degeneration. Prog Brain Res. 1998;117:473–84PubMedCrossRefGoogle Scholar
  24. 24.
    Lowenstein PR, Southgate TD, Smith-Arica JR, Smith J, Castro MG. Gene therapy for inherited neurological disorders: towards therapeutic intervention in the Lesch-Nyhan syndrome. Prog Brain Res. 1998;117:485–501PubMedCrossRefGoogle Scholar
  25. 25.
    Kohn DB, Bauer G, Rice CR, Rothschild JC, Carbonaro DA, Valdez P, Hao Ql, Zhou C, Banner I, Kearns K, Brody K, Fox S, Haden E, Wilson K, Salata C, Dolan C, Wetter C, Aguilar-Cordova E, Church J. A clinical trial of retroviral-mediated transfer of a rev-responsive element decoy gene into CD34(+) cells from the bone marrow of human immunodeficiency virus 1-infected children. Blood. 1999;94 (1):368–71.PubMedGoogle Scholar
  26. 26.
    Amado RG, Mitsuyasu RT, Zack JA. Gene therapy for the treatment of AIDS: animal models and human clinical experience. Front Biosci. 1999;4:D468–75PubMedCrossRefGoogle Scholar
  27. 27.
    Lamothe B, Joshi S. Current developments and future prospects for HIV gene therapy using interfering RNA-based strategies. Front Biosci. 2000;5:D527–55PubMedCrossRefGoogle Scholar
  28. 28.
    Gene Therapy - a loss of innocence. Nature Medicine 2000; 6(1)1Google Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Mark Lawler
    • 1
  1. 1.Department of Haematology, St Patrick Dun Research LabsSt James’s Hospital and Trinity College DublinDublin 8Ireland

Personalised recommendations