Rationale for the use of Gene Therapy for Critical Illness

  • Kenneth L. Brigham
  • Roberto Cruz-Gervis


Management of critically ill patients includes many challenges for physicians dedicated to their care. Treating these patients is complex, not only because of the acute and continuously changing manifestations of severe illnesses, but also because of the various complications that arise from invasive monitoring and therapy. Much progress has been made since the advent of Intensive Care Units (ICUs), mainly through improved supportive care. Even though current ICU care has translated into a reduction in ICU mortality, not much ground has been gained in the management of the specific disease processes that contribute to ICU mortality. Among these disease processes, acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), septic shock and multiple organ dysfunction syndrome (MODS) are clearly the most common contributors to unfavorable outcomes. Despite the institution of standard therapy aimed at the underlying process, many patients die secondary to the deleterious effects of the exaggerated systemic inflammatory response and end-organ damage seen in these disease states.


Gene Therapy Acute Lung Injury Acute Respiratory Distress Syndrome Critical Illness Adult Respiratory Distress Syndrome 
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.

Literature Cited

  1. 1.
    Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J Med. 1999;340:207–14.PubMedCrossRefGoogle Scholar
  2. 2.
    Henson PM, Doherty DE, Riches DW, Worthen GS. LPS and cytokines in lung injury. In: Brigham KL, ed. Endotoxin and the Lungs. New York: Marcel Dekker, Inc, 1994:267–304.Google Scholar
  3. 3.
    McFeely JE, Hudson LD. Sepsis, multiple-organ dysfunction syndrome, and adult respiratory distress syndrome in humans. In: Brigham KL, ed. Endotoxin and the Lungs. New York: Marcel Dekker, Inc, 1994:321–50.Google Scholar
  4. 4.
    Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334–49.PubMedCrossRefGoogle Scholar
  5. 5.
    Sharar SR, Winn RK, Harlan JM. Endotoxin-induced interactions of inflammatory cells with the lungs. In: Brigham KL, ed. Endotoxin and the Lungs. New York: Marcel Dekker, Inc, 1994:229–65.Google Scholar
  6. 6.
    Artigas A, Bernard GR, Carlet J, et al. The American-European Consensus Conference on ARDS, Part 2: ventilatory, pharmacologic, supportive therapy, study design strategies and issues related to recovery and remodeling. Int Care Med. 1998;24:378–98.CrossRefGoogle Scholar
  7. 7.
    Weiss SJ. Tissue destruction by neutrophils. N Engl J Med. 1989;320:365–76.PubMedCrossRefGoogle Scholar
  8. 8.
    Repine JE, Parsons PE. Oxidant-antioxidant balance in endotoxin-induced oxidative injury and tolerance to oxidative injury. In: Brigham KL, ed. Endotoxin and the Lungs. New York: Marcel Dekker, Inc, 1994:207–28.Google Scholar
  9. 9.
    Ziegler EJ, Fisher CJ, Sprung CL, et al. Treatment of Gram-negative bacteremia and septic shock with HA1-A human monoclonal antibody against endotoxin: a randomized, double-blind, placebo-controlled trial. N Engl J Med. 1991;324:429–36.PubMedCrossRefGoogle Scholar
  10. 10.
    The National Committee for the Evaluation of Centoxin. The French National registry of HA-1A (Centoxin) in septic shock: a cohort study of 600 patients. Arch Intern Med. 1994;154:2484–91.CrossRefGoogle Scholar
  11. 11.
    Greenman RL, Shein RMH, Martin MA, et al. A controlled clinical trial of murine monoclonal IGM antibody to endotoxin in the treatment of Gram-negative sepsis. JAMA 1991;266:1097–102.PubMedCrossRefGoogle Scholar
  12. 12.
    Bernard GR, Luce JM, Sprung CL, et al. High-dose corticosteroids in patients with the adult respiratory distress syndrome. N Engl J Med. 1987;317:1565–70.PubMedCrossRefGoogle Scholar
  13. 13.
    Bernard GR, Wheeler AP, Russell JA, et al. The effects of ibuprofen on the physiology and survival of patients with sepsis. N Engl J Med. 1997;336:912–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Fisher CJ Jr, Agosti JM, Opal SM, et al. Treatment of septic shock with tumor necrosis factor receptor:Fc fusion protein. N Engl J Med. 1996;334:1697–702.PubMedCrossRefGoogle Scholar
  15. 15.
    Bone RC, Slotman G, Maunder R, et al. Randomized double-blind, multicenter study of prostaglandin Ei in patients with the adult respiratory distress syndrome. Chest. 1989;96:114–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Fein AM, Bernard GR, Criner GJ, et al. Treatment of severe systemic inflammatory response syndrome and sepsis with a novel bradykinin antagonist, Deltibant (CP-0127): results of a randomized, double-blind, placebo-controlled trial. JAMA. 1997;277:482–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Bernard GR, Wheeler AP, Arons MM, et al. A trial of antioxidants N-acetylcysteine and procysteine in ARDS. Chest. 1997;112:164–72.PubMedCrossRefGoogle Scholar
  18. 18.
    Chiocca S, Cotten M. Cellular responses to adenovirus entry. In: Brigham KL, ed. Gene Therapy for Diseases of the Lung. New York: Marcel Dekker, Inc, 1997:83–92.Google Scholar
  19. 19.
    Liu M, Slutsky AS. Anti-inflammatory therapies: application of molecular biology techniques in intensive care medicine. Int Care Med. 1997;23:718–31.CrossRefGoogle Scholar
  20. 20.
    Brigham KL. Gene therapy for acute diseases of the lungs. In: Brigham KL ed. Gene Therapy for Diseases of the Lung. New York: Marcel Dekker, Inc, 1997:309–22.Google Scholar
  21. 21.
    Canonico AE, Plitman JD, Conary JT, Meyrick BO, Brigham KL. No lung toxicity after repeated aerosol or intravenous delivery of plasmid-cationic liposome complexes. Am J Physiol. 1994;77:415–9.Google Scholar
  22. 22.
    Brigham K, Meyric B, Christman B, Magnuson M, King G, Berry LC Jr. Rapid communication: in vivo transfection of murine lungs with a functioning prokaryotic gene using a liposome vehicle. Am J Med Sci. 1989;298:278–81.PubMedCrossRefGoogle Scholar
  23. 23.
    Brigham KL, Meyrick B, Christman B, et al. Expression of human growth hormone fusion genes in cultured lung endothelial cells and in the lungs of mice. Am JRespir Cell Mol Biol. 1993;8:209–13.Google Scholar
  24. 24.
    Canonico AE, Conary JT, Meyrick BO, Brigham, KL. Aerosol and intravenous transfection of human a 1-antitrypsin gene to lungs of rabbits. Am JRespir Cell Mol Biol. 1994; 10:24–9.Google Scholar
  25. 25.
    Persmark M, Canonico A, Brigham KL, Stecenko AA. Inhibition of respiratory syncytial virus (RSV) infectivity by liposomal-mediated antiprotease gene transfer. J Invest Med. 1995;43:220A.Google Scholar
  26. 26.
    Brigham KL, Stecenko AA. Gene therapy for acute lung injury. Int Care Med. 2000;26:S119–23.CrossRefGoogle Scholar
  27. 27.
    Conary JT, Parker RE, Christman, et al. Protection of rabbit lungs from endotoxin injury by in vivo hyperexpression of the prostaglandin G/H synthase gene. J Clin Invest. 1994;93:1834–40.PubMedCrossRefGoogle Scholar
  28. 28.
    Canonico AE, Conary JT, Meyrick BO, Brigham KL. Aerosol and intravenous transfection of human a 1-antitrypsin to lungs of rabbits. Am J Respir Cell Mol Biol. 1994;10:24–9.PubMedGoogle Scholar
  29. 29.
    Brigham KL, Lane KB, Meyrick B, et al. Transfection of nasal mucosa with a normal α1 antitrypsin-deficient subjects: comparison with protein therapy. Hum Gene Ther. 2000; 11:1023–32.PubMedCrossRefGoogle Scholar
  30. 30.
    Lalani I, Bhol K, Ahmed AR. Interleukin-10: biology, role in inflammation and autoimmunity. Ann Allergy Asthma Immunol. 1997;79:469–84.PubMedCrossRefGoogle Scholar
  31. 31.
    de Vries JE. Immunosuppressive and anti-inflammatory properties of interleukin-10. Ann Med. 1995;27:537–41.PubMedCrossRefGoogle Scholar
  32. 32.
    Chernoff AE, et al. A randomized, controlled trial of IL-10 in humans: inhibition of inflammatory cytokine production and immune responses. J Immunol. 1995;154:5492–99.PubMedGoogle Scholar
  33. 33.
    van Deventer SJ, Elson CO, Fedorak RN. Multiple doses of intravenous interleukin 10 in steroid-refractory Crohn s disease. Gastroenterology. 1997;113:383–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Xing Z, Ohkawara Y, Jordana M, Graham FL, Gauldie J. Adenoviral vector-mediated interleukin-10 expression in vivo: intramuscular gene transfer inhibits cytokine responses in endotoxemia. Gene Ther. 1997;4:140–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Rogy MA, et al. Human tumor necrosis factor receptor (p55) and interleukin-10 gene transfer in the mouse reduces mortality to lethal endotoxemia and also attenuates local inflammatory responses. J Exp Med. 1995;181:2289–93.PubMedCrossRefGoogle Scholar
  36. 36.
    Long W, Thompson T, Sundell H, Schumacher R, Volberg F, Guthrie R. Effects of two rescue doses of a synthetic surfactant on mortality rate and Rationale for Gene Therapy for Critical Illness survival without bronchopulmonary dysplasia in 700- to 1350- gram infants with respiratory distress syndrome. J Pediatr. 1991;118:595–605.PubMedCrossRefGoogle Scholar
  37. 37.
    Anzueto A, Baughman RP, Guntupalli KK, et al. Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. N Engl J Med. 1996;334:1417–21.PubMedCrossRefGoogle Scholar
  38. 38.
    Korst RJ, Bewig B, Crystal RG. In vitro and in vivo transfer and expression of human surfactant SP-A and SP-B-associated protein cDNAs mediated by replication-deficient, recombinant adenoviral vectors. Hum Gene Ther. 1995;6:277–87.PubMedCrossRefGoogle Scholar
  39. 39.
    Yei S, Bachurski CJ, Weaver TE, Wert SE, Trapnell BC, Whitsett JA. Adenoviral-mediated gene transfer of human surfactant protein B to respiratory epithelial cells. Am J Respir Cell Mol Biol. 1994; 11:329–36.PubMedGoogle Scholar
  40. 40.
    Epperly M, Bray J, Zwacka R, Engelhardt J, Travis E, Greenberger J. Prevention of late effects of irradiation lung damage by manganese superoxide dismutase gene therapy. Gene Therapy. 1998;5:196–208.PubMedCrossRefGoogle Scholar
  41. 41.
      . Danel C, Erzurum SC, Prayssac P, et al. Gene therapy for oxidant injury-related diseases: adenovirus-mediated transfer of superoxide dismutase and catalase cDNAs protects against hyperoxia but not against ischemia-reperfusion lung injury. Hum Gene Ther. 1998;9:1487–96.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Kenneth L. Brigham
    • 1
  • Roberto Cruz-Gervis
    • 1
  1. 1.Vanderbilt UniversityNashvilleUSA

Personalised recommendations