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Design of Gene Therapy Trials in CF Patients

  • Jane C. DaviesEmail author
  • Eric W.F.W. Alton
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 741)

Abstract

The report of the first CF patients to receive CFTR gene therapy appeared in 1993; since then, there have been over 20 clinical trials of both viral and non-viral gene transfer agents. These have largely been single dose to either nose or lower airway and have been designed around molecular or bioelectrical outcome measures. Both transgene mRNA and partial correction of chloride secretion have been reported, although sodium hyperabsorption has not been improved. The UK CF Gene Therapy Consortium is focussed on a clinical programme to establish whether these proof-of-principle measures translate into clinical benefit. Here, we discuss the considerations in designing such a programme, focusing in particular on our choice of the optimal, currently available delivery method and established and novel outcome measures. We highlight the logistic and regulatory complexities of such a clinical programme and finally, we look to the future and consider possible alternative strategies.

Key words

CFTR clinical trial gene delivery gene transfer outcome measures vector 

References

  1. 1.
    Engelhardt, J. F., Yankaskas, J. R., Ernst, S. A., Yang, Y., Marino, C. R., Boucher, R. C., et al. (1992) Submucosal glands are the predominant site of CFTR expression in the human bronchus. Nat. Genet. 2, 240–248.PubMedCrossRefGoogle Scholar
  2. 2.
    Engelhardt, J. F., Zepeda, M., Cohn, J. A., Yankaskas, J. R., and Wilson, J. M. (1994) Expression of the cystic fibrosis gene in adult human lung. J. Clin. Invest. 93, 737–749.PubMedCrossRefGoogle Scholar
  3. 3.
    Rawlins, E. L., and Hogan, B. L. (2008) Ciliated epithelial cell lifespan in the mouse trachea and lung. Am. J. Physiol. Lung Cell. Mol. Physiol. 295, L231–234.PubMedCrossRefGoogle Scholar
  4. 4.
    Johnson, L. G., Boyles, S. E., Wilson, J., and Boucher, R. C. (1995) Normalization of raised sodium absorption and raised calcium-mediated chloride secretion by adenovirus-mediated expression of cystic fibrosis transmembrane conductance regulator in primary human cystic fibrosis airway epithelial cells. J. Clin. Invest. 95, 1377–1382.PubMedCrossRefGoogle Scholar
  5. 5.
    Zhang, Y., Jiang, Q., Dudus, L., Yankaskas, J. R., and Engelhardt, J. F. (1998) Vector-specific complementation profiles of two independent primary defects in cystic fibrosis airways. Hum. Gene Ther. 9, 635–648.PubMedCrossRefGoogle Scholar
  6. 6.
    Gan, K. H., Veeze, H. J., van den Ouweland, A. M., Halley, D. J., Scheffer, H., van der Hout, A., et al. (1995) A cystic fibrosis mutation associated with mild lung disease. N. Engl. J. Med. 333, 95–99.PubMedCrossRefGoogle Scholar
  7. 7.
    Zhang, L., Button, B., Gabriel, S. E., Burkett, S., Yan, Y., Skiadopoulos, M. H. et al. (2009) CFTR delivery to 25% of surface epithelial cells restores normal rates of mucus transport to human cystic fibrosis airway epithelium. PLoS Biol. 7, e1000155.PubMedCrossRefGoogle Scholar
  8. 8.
    Zabner, J., Ramsey, B. W., Meeker, D. P., Aitken, M. L., Balfour, R. P., Gibson, R. L., et al. (1996) Repeat administration of an adenovirus vector encoding cystic fibrosis transmembrane conductance regulator to the nasal epithelium of patients with cystic fibrosis. J. Clin. Invest. 97, 1504–1511.PubMedCrossRefGoogle Scholar
  9. 9.
    Harvey, B. G., Leopold, P. L., Hackett, N. R., Grasso, T. M., Williams, P. M., Tucker, A. L., et al. (1999) Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus. J. Clin. Invest. 104, 1245–1255.PubMedCrossRefGoogle Scholar
  10. 10.
    Moss, R. B., Rodman, D., Spencer, L. T., Aitken, M. L., Zeitlin, P. L., Waltz, D., et al. (2004) Repeated adeno-associated virus serotype 2 aerosol-mediated cystic fibrosis transmembrane regulator gene transfer to the lungs of patients with cystic fibrosis: a multicenter, double-blind, placebo-controlled trial. Chest 125, 509–521.PubMedCrossRefGoogle Scholar
  11. 11.
    Moss, R. B., Milla, C., Colombo, J., Accurso, F., Zeitlin, P. L., Clancy, J. P., et al. (2007) Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis: a randomized placebo-controlled phase 2B trial. Hum. Gene Ther. 18, 726–732.PubMedCrossRefGoogle Scholar
  12. 12.
    Hyde, S. C., Southern, K. W., Gileadi, U., Fitzjohn, E. M., Mofford, K. A., Waddell, B. E., et al. (2000) Repeat administration of DNA/liposomes to the nasal epithelium of patients with cystic fibrosis. Gene Ther. 7, 1156–1165.Google Scholar
  13. 13.
    Thrasher, A. J., Gaspar, H. B., Baum, C., Modlich, U., Schambach, A., Candotti, F., et al. (2006) Gene therapy: X-SCID transgene leukaemogenicity. Nature 443, E5–E7.CrossRefGoogle Scholar
  14. 14.
    Walters, R. W., Grunst, T., Bergelson, J. M., Finberg, R. W., Welsh, M. J., and Zabner, J. (1999) Basolateral localization of fiber receptors limits adenovirus infection from the apical surface of airway epithelia. J. Biol. Chem. 274, 10219–10226.PubMedCrossRefGoogle Scholar
  15. 15.
    Crystal, R. G., McElvaney, N. G., Rosenfeld, M. A., Chu, C. S., Mastrangeli, A., Hay, J. G., et al. (1994) Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis. Nat. Genet. 8, 42–51.PubMedCrossRefGoogle Scholar
  16. 16.
    Caplen, N. J., Alton, E. W., Middleton, P. G., Dorin, J. R., Stevenson, B. J., Gao, X., et al. (1995) Liposome-mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis. Nat. Med. 1, 39–46.PubMedCrossRefGoogle Scholar
  17. 17.
    Gill, D. R., Southern, K. W., Mofford, K. A., Seddon, T., Huang, L., Sorgi, F., et al. (1997) A placebo-controlled study of liposome-mediated gene transfer to the nasal epithelium of patients with cystic fibrosis. Gene Ther. 4, 199–209.PubMedCrossRefGoogle Scholar
  18. 18.
    Porteous, D. J., Dorin, J. R., McLachlan, G., Davidson-Smith, H., Davidson, H., Stevenson, B. J., et al. (1997) Evidence for safety and efficacy of DOTAP cationic liposome mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis. Gene Ther. 4, 210–218.PubMedCrossRefGoogle Scholar
  19. 19.
    Zabner, J., Cheng, S. H., Meeker, D., Launspach, J., Balfour, R., Perricone, M. A., et al. (1997) Comparison of DNA-lipid complexes and DNA alone for gene transfer to cystic fibrosis airway epithelia in vivo. J. Clin. Invest. 100, 1529–1537.PubMedCrossRefGoogle Scholar
  20. 20.
    Alton, E. W., Stern, M., Farley, R., Jaffe, A., Chadwick, S. L., Phillips, J., et al. (1999) Cationic lipid-mediated CFTR gene transfer to the lungs and nose of patients with cystic fibrosis: a double-blind placebo-controlled trial. Lancet 353, 947–954.PubMedCrossRefGoogle Scholar
  21. 21.
    Ruiz, F. E., Clancy, J. P., Perricone, M. A., Bebok, Z., Hong, J. S., Cheng, S. H., et al. (2001) A clinical inflammatory syndrome attributable to aerosolized lipid-DNA administration in cystic fibrosis. Hum. Gene Ther. 12, 751–761.PubMedCrossRefGoogle Scholar
  22. 22.
    Konstan, M. W., Davis, P. B., Wagener, J. S., Hilliard, K. A., Stern, R. C., Milgram, L. J., et al. (2004) Compacted DNA nanoparticles administered to the nasal mucosa of cystic fibrosis subjects are safe and demonstrate partial to complete cystic fibrosis transmembrane regulator reconstitution. Hum. Gene Ther. 15, 1255–1269.PubMedCrossRefGoogle Scholar
  23. 23.
    Wagner, J. A., Messner, A. H., Moran, M. L., Daifuku, R., Kouyama, K., Desch, J. K., et al. (1999) Safety and biological efficacy of an adeno-associated virus vector-cystic fibrosis transmembrane regulator (AAV-CFTR) in the cystic fibrosis maxillary sinus. Laryngoscope 109, 266–274.PubMedCrossRefGoogle Scholar
  24. 24.
    Kälin, N., Claass, A., Sommer, M., Puchelle, E., and Tümmler, B. (1999) DeltaF508 CFTR protein expression in tissues from patients with cystic fibrosis. J. Clin. Invest. 103, 1379–1389.PubMedCrossRefGoogle Scholar
  25. 25.
    Carvalho-Oliveira, I., Efthymiadou, A., Malhó, R., Nogueira, P., Tzetis, M., Kanavakis, E., et al. (2004) CFTR localization in native airway cells and cell lines expressing wild-type or F508del-CFTR by a panel of different antibodies. J. Histochem. Cytochem. 52, 193–203.PubMedCrossRefGoogle Scholar
  26. 26.
    Davidson, H., Wilson, A., Gray, R. D., Horsley, A., Pringle, I. A., McLachlan, G., et al. (2009) An immunocytochemical assay to detect human CFTR expression following gene transfer. Mol. Cell Probes 23, 272–280.PubMedCrossRefGoogle Scholar
  27. 27.
    Middleton, P. G., Geddes, D. M., and Alton, E. W. (1994) Protocols for in vivo measurement of the ion transport defects in cystic fibrosis nasal epithelium. Eur. Respir. J. 7, 2050–2056.PubMedCrossRefGoogle Scholar
  28. 28.
    Standaert, T. A., Boitano, L., Emerson, J., Milgram, L. J., Konstan, M. W., Hunter, J., et al. (2004) Standardized procedure for measurement of nasal potential difference: an outcome measure in multicenter cystic fibrosis clinical trials. Pediatr. Pulmonol. 37, 385–392.PubMedCrossRefGoogle Scholar
  29. 29.
    Clancy, J. P., Rowe, S. M., Bebok, Z., Aitken, M. L., Gibson, R., Zeitlin, P., et al. (2007) No detectable improvements in cystic fibrosis transmembrane conductance regulator by nasal aminoglycosides in patients with cystic fibrosis with stop mutations. Am. J. Respir. Cell. Mol. Biol. 37, 57–66.PubMedCrossRefGoogle Scholar
  30. 30.
    Yaakov, Y., Kerem, E., Yahav, Y., Rivlin, J., Blau, H., Bentur, L., et al. (2007) Reproducibility of nasal potential difference measurements in cystic fibrosis. Chest 132, 1219–1226.PubMedCrossRefGoogle Scholar
  31. 31.
    Davies, J. C., Davies, M., McShane, D., Smith, S., Chadwick, S., Jaffe, A., et al. (2005) Potential difference measurements in the lower airway of children with and without cystic fibrosis. Am. J. Respir. Cell. Mol. Biol. 171, 1015–1019.Google Scholar
  32. 32.
    Wagner, J. A., Nepomuceno, I. B., Messner, A. H., Moran, M. L., Batson, E. P., Dimiceli, S., et al. (2002) A phase II, double-blind, randomized, placebo-controlled clinical trial of tgAAVCF using maxillary sinus delivery in patients with cystic fibrosis with antrostomies. Hum. Gene Ther. 13, 1349–1359.Google Scholar
  33. 33.
    Knowles, M. R., Hohneker, K. W., Zhou, Z., Olsen, J. C., Noah, T. L., Hu, P. C., et al. (1995) A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis. N. Engl. J. Med. 333, 823–831.PubMedCrossRefGoogle Scholar
  34. 34.
    Zuckerman, J. B., Robinson, C. B., McCoy, K. S., Shell, R., Sferra, T. J., Chirmule, N., et al. (1999) 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. 10, 2973–2985.PubMedCrossRefGoogle Scholar
  35. 35.
    Joseph, P. M., O’Sullivan, B. P., Lapey, A., Plog, M. S., O’Sullivan, B. P., Joseph, P. M., et al. (2001) Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. I. Methods, safety, and clinical implications. Hum. Gene Ther. 12, 1369–1382.PubMedCrossRefGoogle Scholar
  36. 36.
    Perricone, M. A., Morris, J. E., Pavelka, K., Plog, M. S, O’Sullivan, B. P., Joseph, P. M., et al. (2001) Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. II. Transfection efficiency in airway epithelium. Hum. Gene Ther. 12, 1383–1394.PubMedCrossRefGoogle Scholar
  37. 37.
    Aitken, M. L., Moss, R. B., Waltz, D. A., and Dovey, M. E. Tonelli, M. R., McNamara, S. C., et al. (2001) A phase I study of aerosolized administration of tgAAVCF to cystic fibrosis subjects with mild lung disease. Hum. Gene Ther. 12, 1907–1916.PubMedCrossRefGoogle Scholar
  38. 38.
    Flotte, T. R., Zeitlin, P. L., Reynolds, T. C., Heald, A. E., Pedersen, P., Beck, S., et al. (2003) Phase I trial of intranasal and endobronchial administration of a recombinant adeno-associated virus serotype 2 (rAAV2)-CFTR vector in adult cystic fibrosis patients: a two-part clinical study. Hum. Gene Ther. 14, 1079–1088.PubMedCrossRefGoogle Scholar
  39. 39.
    Yew, N. S., and Cheng, S. H. (2004) Reducing the immunostimulatory activity of CpG-containing plasmid DNA vectors for non-viral gene therapy. Expert Opin. Drug Deliv. 1, 115–125.PubMedCrossRefGoogle Scholar
  40. 40.
    Hyde, S. C., Pringle, I. A., Abdullah, S., Lawton, A. E., Davies, L. A., Varathalingam, A., et al. (2008) CpG-free plasmids confer reduced inflammation and sustained pulmonary gene expression. Nat. Biotechnol. 26, 549–551.PubMedCrossRefGoogle Scholar
  41. 41.
    Davis, P. B., Byard, P. J., and Konstan, M. W. (1997) Identifying treatments that halt progression of pulmonary disease in cystic fibrosis. Pediatr. Res. 41, 161–165.PubMedCrossRefGoogle Scholar
  42. 42.
    Zabner, J., Couture, L. A., Gregory, R. J., Graham, S. M., Smith, A. E., and Welsh, M. J. (1993) Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis. Cell 75, 207–216.PubMedCrossRefGoogle Scholar
  43. 43.
    Hay, J. G., McElvaney, N. G., Herena, J., and Crystal, R. G. (1995) Modification of nasal epithelial potential differences of individuals with cystic fibrosis consequent to local administration of a normal CFTR cDNA adenovirus gene transfer vector. Hum. Gene Ther. 6, 1487–1496.PubMedCrossRefGoogle Scholar
  44. 44.
    Bellon, G., Michel-Calemard, L., Thouvenot, D., Jagneaux, V., Poitevin, F., Malcus, C., et al. (1997) Aerosol administration of a recombinant adenovirus expressing CFTR to cystic fibrosis patients: a phase I clinical trial. Hum. Gene Ther. 8, 15–25.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Gene TherapyImperial College LondonLondonUK

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