Skip to main content

Advertisement

SpringerLink
Log in

Gene Therapy for Allergic Airway Diseases

  • Published:
Current Allergy and Asthma Reports Aims and scope Submit manuscript

Abstract

Airway diseases such as allergic asthma and rhinitis are characterized by a T-helper type 2 (Th2) response. Treatment of allergic airway diseases is currently limited to drugs that relieve disease symptoms and inflammation. In the search for new therapeutics, efforts have been made to treat allergic airway disease with gene therapy, and many preclinical studies have demonstrated its impressive potential. Most strategies focus on blocking the expression of proinflammatory proteins or transcription factors involved in the disease pathogenesis using antisense oligonucleotides, DNAzymes, small interfering RNA, or blocking of microRNAs using antagomirs. Changing the Th1/Th2 balance by overexpressing Th1-stimulating factors is another treatment option. Although the proof of concept is convincing in animal models, progress in humans remains limited. In this review, we focus on preclinical models to describe the recent developments and major breakthroughs for treating allergic airway diseases with gene therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Holgate ST, Polosa R: Treatment strategies for allergy and asthma. Nat Rev Immunol 2008; 8:218–230.

    Article  PubMed  CAS  Google Scholar 

  2. •• Barnes PJ: New therapies for asthma: is there any progress? Trends Pharmacol Sci 2010; 31:335–343. This is a state-of-the-art review on current and future therapies for asthma.

    Article  PubMed  CAS  Google Scholar 

  3. Bateman ED, Boushey HA, Bousquet J, et al.: Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004; 170:836–844.

    Article  PubMed  Google Scholar 

  4. Park SJ, Lee YC: Interleukin-17 regulation: an attractive therapeutic approach for asthma. Respir Res 2010; 11:78.

    Article  PubMed  Google Scholar 

  5. Gill DR, Bazzani RP, Hyde SC: Strategies for long-term expression of transgenes in the respiratory epithelium. Curr Opin Mol Ther 2010; 12:386–393.

    PubMed  CAS  Google Scholar 

  6. •• Griesenbach U, Alton EW: Gene transfer to the lung: lessons learned from more than 2 decades of CF gene therapy. Adv Drug Deliv Rev 2009; 61:128–139. This is an excellent comprehensive review on the progress and pitfalls for acquiring gene transfer to the lungs.

    Article  PubMed  CAS  Google Scholar 

  7. Popescu FD, Popescu F: A review of antisense therapeutic interventions for molecular biological targets in asthma. Biologics 2007; 1:271–283.

    PubMed  CAS  Google Scholar 

  8. Sel S, Wegmann M, Dicke T, et al.: Effective prevention and therapy of experimental allergic asthma using a GATA-3-specific DNAzyme. J Allergy Clin Immunol 2008; 121:910–916.

    Article  PubMed  CAS  Google Scholar 

  9. Mattes J, Yang M, Foster PS: Regulation of microRNA by antagomirs: a new class of pharmacological antagonists for the specific regulation of gene function? Am J Respir Cell Mol Biol 2007; 36:8–12.

    Article  PubMed  CAS  Google Scholar 

  10. • Suzuki M, Zheng X, Zhang X, et al.: A novel allergen-specific therapy for allergy using CD40-silenced dendritic cells. J Allergy Clin Immunol 2010; 125:737–43, 743. This study demonstrated that local treatment with CD40-silenced dendritic cells can reduce allergic symptoms and responses in vivo.

    Article  PubMed  CAS  Google Scholar 

  11. Haldar P, Brightling CE, Hargadon B, et al.: Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009; 360:973–984.

    Article  PubMed  CAS  Google Scholar 

  12. Huang HY, Lee CC, Chiang BL: Small interfering RNA against interleukin-5 decreases airway eosinophilia and hyper-responsiveness. Gene Ther 2008; 15:660–667.

    Article  PubMed  CAS  Google Scholar 

  13. Zeng D, Cao Y, Song Q, et al.: Effects of antisense interleukin-5 gene transferred by recombinant adeno-associated virus to allergic rats. Respirology 2010; 15:132–140.

    Article  PubMed  Google Scholar 

  14. Zeng D, Cao Y, Song Q, et al.: Recombinant Adeno-associated virus vector-mediated delivery of antisense interleukin-5 gene attenuates airway remodeling in allergic rats. Int Arch Allergy Immunol 2010; 154:207–215.

    Article  PubMed  Google Scholar 

  15. Cao Y, Zeng D, Song Q, et al.: The effects of antisense interleukin-4 gene transferred by recombinant adeno-associated virus vector on the airway remodeling in allergic rats. J Asthma 2010; 47:951–958.

    PubMed  CAS  Google Scholar 

  16. Karras JG, Crosby JR, Guha M, et al.: Anti-inflammatory activity of inhaled IL-4 receptor-alpha antisense oligonucleotide in mice. Am J Respir Cell Mol Biol 2007; 36:276–285.

    Article  PubMed  CAS  Google Scholar 

  17. Clinical Trial: A Phase 1 Study of AIR645 in Healthy Subjects and Subjects With Controlled Asthma (AIR645-CS1). Available at: http://www.clinicaltrials.gov/ct2/show/NCT00658749. Accessed November 2010.

  18. Seguin RM, Ferrari N: Emerging oligonucleotide therapies for asthma and chronic obstructive pulmonary disease. Expert Opin Investig Drugs 2009; 18:1505–1517.

    Article  PubMed  CAS  Google Scholar 

  19. •• Gauvreau GM, Boulet LP, Cockcroft DW, et al.: Antisense therapy against CCR3 and the common beta chain attenuates allergen-induced eosinophilic responses. Am J Respir Crit Care Med 2008; 177:952–958. This is the first clinical study to demonstrate beneficial effects of antisense therapy in mild asthmatics.

    Article  PubMed  CAS  Google Scholar 

  20. Clinical trial: Efficacy and safety of four escalating dose regimens of TPI ASM8 in patients with allergic asthma. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00822861. Accessed November 2010.

  21. Chatila TA, Li N, Garcia-Lloret M, et al.: T-cell effector pathways in allergic diseases: transcriptional mechanisms and therapeutic targets. J Allergy Clin Immunol 2008; 121:812–823.

    Article  PubMed  CAS  Google Scholar 

  22. Oh CK, Geba GP, Molfino N: Investigational therapeutics targeting the IL-4/IL-13/STAT-6 pathway for the treatment of asthma. Eur Respir Rev 2010; 19:46–54.

    Article  PubMed  CAS  Google Scholar 

  23. Kuperman DA, Huang X, Koth LL, et al.: Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat Med 2002; 8:885–889.

    PubMed  CAS  Google Scholar 

  24. Walker W, Healey GD, Hopkin JM: RNA interference of STAT6 rapidly attenuates ongoing interleukin-13-mediated events in lung epithelial cells. Immunology 2009; 127:256–266.

    Article  PubMed  CAS  Google Scholar 

  25. • Darcan-Nicolaisen Y, Meinicke H, Fels G, et al.: Small interfering RNA against transcription factor STAT6 inhibits allergic airway inflammation and hyperreactivity in mice. J Immunol 2009; 182:7501-7508. This is the first preclinical study to demonstrate that STAT6 siRNA can reduce allergic inflammation in mice.

    Article  PubMed  CAS  Google Scholar 

  26. Hosoya K, Satoh T, Yamamoto Y, et al.: Gene silencing of STAT6 with siRNA ameliorates contact hypersensitivity and allergic rhinitis. Allergy 2010; Epub ahead of print.

  27. Finotto S, De Sanctis GT, Lehr HA, et al.: Treatment of allergic airway inflammation and hyperresponsiveness by antisense-induced local blockade of GATA-3 expression. J Exp Med 2001; 193:1247–1260.

    Article  PubMed  CAS  Google Scholar 

  28. Lee CC, Huang HY, Chiang BL: Lentiviral-mediated GATA-3 RNAi decreases allergic airway inflammation and hyperresponsiveness. Mol Ther 2008; 16:60–65.

    Article  PubMed  CAS  Google Scholar 

  29. Edwards MR, Bartlett NW, Clarke D, et al.: Targeting the NF-kappaB pathway in asthma and chronic obstructive pulmonary disease. Pharmacol Ther 2009; 121:1–13.

    Article  PubMed  CAS  Google Scholar 

  30. Choi IW, Kim DK, Ko HM, Lee HK: Administration of antisense phosphorothioate oligonucleotide to the p65 subunit of NF-kappaB inhibits established asthmatic reaction in mice. Int Immunopharmacol 2004; 4:1817–1828.

    Article  PubMed  CAS  Google Scholar 

  31. Desmet C, Gosset P, Pajak B, et al.: Selective blockade of NF-kappa B activity in airway immune cells inhibits the effector phase of experimental asthma. J Immunol 2004; 173:5766–5775.

    PubMed  CAS  Google Scholar 

  32. Desmet C, Gosset P, Henry E, et al.: Treatment of experimental asthma by decoy-mediated local inhibition of activator protein-1. Am J Respir Crit Care Med 2005; 172:671–678.

    Article  PubMed  Google Scholar 

  33. Quarcoo D, Weixler S, Groneberg D, et al.: Inhibition of signal transducer and activator of transcription 1 attenuates allergen-induced airway inflammation and hyperreactivity. J Allergy Clin Immunol 2004; 114:288–295.

    Article  PubMed  CAS  Google Scholar 

  34. Luhrmann A, Tschernig T, von der LH, et al.: Decoy oligodeoxynucleotide against STAT transcription factors decreases allergic inflammation in a rat asthma model. Exp Lung Res 2010; 36:85–93.

    Article  PubMed  Google Scholar 

  35. Oglesby IK, McElvaney NG, Greene CM: MicroRNAs in inflammatory lung disease—Master regulators or target practice? Respir Res 2010; 11:148.

    Article  PubMed  Google Scholar 

  36. •• Mattes J, Collison A, Plank M, et al.: Antagonism of microRNA-126 suppresses the effector function of TH2 cells and the development of allergic airways disease. Proc Natl Acad Sci U S A 2009; 106:18704–18709. This report demonstrated that targeting miRNAs may be a therapeutic option for treating allergic airway disease.

    Article  PubMed  CAS  Google Scholar 

  37. Lambrecht BN, Hammad H: Biology of lung dendritic cells at the origin of asthma. Immunity 2009; 31:412–424.

    Article  PubMed  CAS  Google Scholar 

  38. Crosby JR, Guha M, Tung D, et al.: Inhaled CD86 antisense oligonucleotide suppresses pulmonary inflammation and airway hyper-responsiveness in allergic mice. J Pharmacol Exp Ther 2007; 321:938–946.

    Article  PubMed  CAS  Google Scholar 

  39. Suzuki M, Zheng X, Zhang X, et al.: Inhibition of allergic responses by CD40 gene silencing. Allergy 2009; 64:387–397.

    Article  PubMed  CAS  Google Scholar 

  40. Cabral MD, Paulet PE, Robert V, et al.: Knocking down Cav1 calcium channels implicated in Th2 cell activation prevents experimental asthma. Am J Respir Crit Care Med 2010; 181:1310–1317.

    Article  PubMed  CAS  Google Scholar 

  41. Stenton GR, Ulanova M, Dery RE, et al.: Inhibition of allergic inflammation in the airways using aerosolized antisense to Syk kinase. J Immunol 2002; 169:1028–1036.

    PubMed  CAS  Google Scholar 

  42. Sanderson MP, Gelling SJ, Rippmann JF, Schnapp A: Comparison of the anti-allergic activity of Syk inhibitors with optimized Syk siRNAs in FcepsilonRI-activated RBL-2H3 basophilic cells. Cell Immunol 2010; 262:28–34.

    Article  PubMed  CAS  Google Scholar 

  43. Lai WQ, Goh HH, Bao Z, et al.: The role of sphingosine kinase in a murine model of allergic asthma. J Immunol 2008; 180:4323–4329.

    PubMed  CAS  Google Scholar 

  44. Yang CJ, Liu YK, Liu CL, et al.: Inhibition of acidic mammalian chitinase by RNA interference suppresses ovalbumin-sensitized allergic asthma. Hum Gene Ther 2009; 20:1597–1606.

    Article  PubMed  CAS  Google Scholar 

  45. Chuang YH, Yang YH, Wu SJ, Chiang BL: Gene therapy for allergic diseases. Curr Gene Ther 2009; 9:185–191.

    Article  PubMed  CAS  Google Scholar 

  46. Tian D, Fu Z, Liu E, et al.: Therapeutic effect of intratracheal administration of murine IL-4 receptor antagonist on asthmatic airway inflammation. J Asthma 2008; 45:715–721.

    Article  PubMed  CAS  Google Scholar 

  47. Li H, Xie Q, Wang H, et al.: Intramuscular delivery of mIL-12 gene reduces the expression of CD44/CD49d on pulmonary leucocytes and inhibits ovalbumin-induced airway hyperreactivity. Inflamm Res 2008; 57:11–17.

    Article  PubMed  CAS  Google Scholar 

  48. Hsu CY, Liu HE, Sheu FY, et al.: Synergistic therapeutic effects of combined adenovirus-mediated interleukin-10 and interleukin-12 gene therapy on airway inflammation in asthmatic mice. J Gene Med 2010; 12:11–21.

    Article  PubMed  CAS  Google Scholar 

  49. Kong X, Hellermann GR, Zhang W, et al.: Chitosan interferon-gamma nanogene therapy for lung disease: modulation of T-cell and dendritic cell immune responses. Allergy Asthma Clin Immunol 2008; 4:95–105.

    Article  PubMed  CAS  Google Scholar 

  50. Wang SY, Yang M, Xu XP, et al.: Intranasal delivery of T-bet modulates the profile of helper T cell immune responses in experimental asthma. J Investig Allergol Clin Immunol 2008; 18:357–365.

    PubMed  CAS  Google Scholar 

  51. Barik S, Bitko V: Prospects of RNA interference therapy in respiratory viral diseases: update 2006. Expert Opin Biol Ther 2006; 6:1151–1160.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Dr. Maes is sponsored by the Interuniversity Attraction Poles Program (Belgian State, Belgian Science Policy, Project P6/35). Dr. Tournoy is a senior clinical investigator granted by FWO Flanders.

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

  1. Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium

    Tania Maes, Kurt G. Tournoy & Guy F. Joos

Authors
  1. Tania Maes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kurt G. Tournoy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guy F. Joos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tania Maes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Maes, T., Tournoy, K.G. & Joos, G.F. Gene Therapy for Allergic Airway Diseases. Curr Allergy Asthma Rep 11, 163–172 (2011). https://doi.org/10.1007/s11882-011-0177-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11882-011-0177-8

Keywords

Search

Navigation