Nature 385, 721 - 725 (20 February 1997); doi:10.1038/385721a0

DNA antisense therapy for asthma in an animal model

Jonathan W. Nyce^*† & W. James Metzger^‡

^*Department of Molecular Pharmacology and Therapeutics, EpiGenesis Pharmaceuticals, Greenville, North Carolina 27834, USA
^‡Department of Medicine, Section of Allergy, Asthma and Immunology, and ^†Department of Pharmacology, School of Medicine, East Carolina University, Greenville, North Carolina 27858, USA

Asthma is an inflammatory disease characterized by bronchial hyper-responsiveness that can proceed to life-threatening airway obstruction. It is one of the most common diseases in industrialized countries, and in the United States accounts for about 1% of all healthcare costs¹. Asthma prevalence and mortality have increased dramatically over the past decade², and occupational asthma is predicted to be the pre-eminent occupational lung disease in the next decade³. Increasing evidence suggests that adenosine, an endogenous purine that is involved in normal physiological processes, may be an important mediator of bronchial asthma^4–15. In contrast to normal individuals, asthmatic individuals respond to adenosine challenge with marked airway obstruction^6,7, and concentrations of adenosine are elevated in the bronchoalveolar lavage fluid of asthma patients⁹. We performed a randomized crossover study using the dust mite-conditioned allergic rabbit model of human asthma. Administration of an aerosolized phosphorothioate antisense oligodeoxynucleotide targeting the adenosine A₁ receptor desensitized the animals to subsequent challenge with either adenosine or dust-mite allergen.

1. Weiss, K. B., Gergen, P. J. & Hodgson, T. A. New Engl. J. Med. 326, 862−866 (1992). | PubMed | ISI | ChemPort |
2. MMWR-Morbidity and Mortality Weekly Report 41, 733−735 (1992).
3. Chan-Yeung, M. & Malo, J. L. Eur. Respir. J. 7, 346−371 (1994). | Article | PubMed | ChemPort |
4. Pauwels, R. A., Kips, J. C. & Joos, G. F. Clin. Exp. Allergy 21 (suppl.), 48−55 (1991). | PubMed |
5. Bjorck, T., Gustafsson, L. E. & Dahlen, S. E. Am. Rev. Respir. Dis. 145, 1087−1091 (1992). | PubMed | ChemPort |
6. Church, M. K. & Holgate, S. T. Trends Pharmacol. Sci. 7, 49−50 (1986). | Article |
7. Cushley, M. J., Tattersfield, A. E. & Holgate, S. T. Br. J. Clin. Pharmacol. 15, 161−165 (1983). | PubMed | ChemPort |
8. Holgate, S. T., Church, M. K. & Polosa, R. Ann. NY Acad. Sci. 629, 227−236 (1991). | PubMed | ChemPort |
9. Driver, A. G., Kukoly, C. A., Ali, S. & Mustafa, S. J. Am. Rev. Respir. Dis. 148, 91−97 (1993). | PubMed | ChemPort |
10. Pauwels, R. A. & Joos, G. F. Arch. Int. Pharmacodyn. Ther. 329, 151−160 (1995). | PubMed | ChemPort |
11. Ali, S., Mustafa, S. J. & Metzger, W. J. Agents Actions 37, 165−176 (1992). | PubMed | ChemPort |
12. Ali, S., Mustafa, S. J. & Metzger, W. J. J. Pharmacol. Exp. Ther. 268, 1328−1334 (1994). | PubMed | ChemPort |
13. Ali, S., Mustafa, S. J. & Metzger, W. J. Am. J. Physiol. 266, L271−L277 (1994). | PubMed | ChemPort |
14. Cushley, M. J., Tattersfield, A. E. & Holgate, S. T. Am. Rev. Respir. Dis. 129, 380−384 (1984). | PubMed | ChemPort |
15. Mann, J. S. & Holgate, S. T. Br. J. Clin. Pharmacol. 19, 685−692 (1985). | PubMed | ChemPort |
16. Wagner, R. W. Nature 372, 333−335 (1994). | Article | PubMed | ISI | ChemPort |
17. Stein, C. A. & Narayanan, R. Curr. Opin. Oncol. 6, 587−594 (1994). | PubMed | ChemPort |
18. Bennett, C. F., Chiang, M. Y., Chan, H., Shoemaker, J. E. & Mirabelli, C. K. Mol. Pharmacol. 41, 1023−1033 (1992). | PubMed | ISI | ChemPort |
19. Saijo, Y., Perlaky, L., Wang, H. & Busch, H. Oncol. Res. 6, 243−249 (1994). | PubMed | ISI | ChemPort |
20. Ross, G. F. et al. Hum. Gene Ther. 6, 31−40 (1995). | PubMed | ChemPort |
21. Pison, U., Neuendank, M. A., Weissbach, S. & Pietschmann, S. Eur. J. Clin. Invest. 24, 586−599 (1994). | PubMed | ISI | ChemPort |
22. Hulsmann, A. R., Raatgeep, H. R., Saxena, P. R., Kerrebijn, K. F. & de Tongate, J. C. M. J. Respir. Crit. Care Med. 150, 1012−1018 (1994). | ChemPort |
23. Tsukagoshi, H., Haddad, E. B., Barnes, P. J. & Chung, G. F. J. Pharmacol. Exp. Ther. 273, 1257−1263 (1995). | PubMed | ChemPort |
24. Feletou, M. et al. Eur. J. Pharmacol. 274, 57−64 (1995). | Article | PubMed | ChemPort |
25. Metzger, W. J. in Late Phase Allergic Reactions (ed. Dorsch, W.) 347−362 (CRC Press, Boca Raton, FL, 1990).
26. Jarvis, M. F. et al. J. Pharmacol. Exp. Ther. 251, 888−893 (1989). | PubMed | ChemPort |
27. Trifilieff, A., DaSilva, A., Landry, Y. & Gles, J. P. J. Pharmacol. Exp. Ther. 263, 1377−1382 (1992). | PubMed | ISI | ChemPort |
28. Bradford, M. M. Anal. Biochem. 72, 240−254 (1976).