A clinical inflammatory syndrome attributable to aerosolized lipid-DNA administration in cystic fibrosis

F. E. Ruiz, J. P. Clancy, M. A. Perricone, Z. Bebok, J. S. Hong, S. H. Cheng, D. P. Meeker, K. R. Young, Robert Schoumacher, M. R. Weatherly, L. Wing, J. E. Morris, L. Sindel, M. Rosenberg, F. W. Van Ginkel, J. R. McGhee, D. Kelly, R. K. Lyrene, E. J. Sorscher

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Abstract

Immunologic reactivity to lipid-DNA conjugates has traditionally been viewed as less of an issue than with viral vectors. We performed a dose escalation safety trial of aerosolized cystic fibrosis transmembrane conductance regulator (CFTR) cDNA to the lower airways of eight adult cystic fibrosis patients, and monitored expression by RT-PCR. The cDNA was complexed to a cationic lipid amphiphile (GL-67) consisting of a cholesterol anchor linked to a spermine head group. CFTR transgene was detected in three patients at 2-7 days after gene administration. Four of the eight patients developed a pronounced clinical syndrome of fever (maximum of 103.3EF), myalgias, and arthralgia beginning within 6 hr of gene administration. Serum IL-6 but not levels of IL-8, IL-1, TNF-α, or IFN-γ became elevated within 1-3 hr of gene administration. No antibodies to the cationic liposome or plasmid DNA were detected. We found that plasmid DNA by itself elicited minimal proliferation of peripheral blood mononuclear cells taken from study patients, but led to brisk immune cell proliferation when complexed to a cationic lipid. Lipid and DNA were synergistic in causing this response. Cellular proliferation was also seen with eukaryotic DNA, suggesting that at least part of the immunologic response to lipid-DNA conjugates is independent of unmethylated (E. coli-derived) CpG sequences that have previously been associated with innate inflammatory changes in the lung.

Original languageEnglish (US)
Pages (from-to)751-761
Number of pages11
JournalHuman Gene Therapy
Volume12
Issue number7
DOIs
StatePublished - Aug 9 2001

Fingerprint

Cystic Fibrosis
Lipids
DNA
Cystic Fibrosis Transmembrane Conductance Regulator
Plasmids
Complementary DNA
Cell Proliferation
Genes
Spermine
Myalgia
Arthralgia
Interleukin-8
Transgenes
Interleukin-1
Liposomes
Interleukin-6
Blood Cells
Fever
Cholesterol
Escherichia coli

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Ruiz, F. E., Clancy, J. P., Perricone, M. A., Bebok, Z., Hong, J. S., Cheng, S. H., ... Sorscher, E. J. (2001). A clinical inflammatory syndrome attributable to aerosolized lipid-DNA administration in cystic fibrosis. Human Gene Therapy, 12(7), 751-761. https://doi.org/10.1089/104303401750148667

A clinical inflammatory syndrome attributable to aerosolized lipid-DNA administration in cystic fibrosis. / Ruiz, F. E.; Clancy, J. P.; Perricone, M. A.; Bebok, Z.; Hong, J. S.; Cheng, S. H.; Meeker, D. P.; Young, K. R.; Schoumacher, Robert; Weatherly, M. R.; Wing, L.; Morris, J. E.; Sindel, L.; Rosenberg, M.; Van Ginkel, F. W.; McGhee, J. R.; Kelly, D.; Lyrene, R. K.; Sorscher, E. J.

In: Human Gene Therapy, Vol. 12, No. 7, 09.08.2001, p. 751-761.

Research output: Contribution to journalArticle

Ruiz, FE, Clancy, JP, Perricone, MA, Bebok, Z, Hong, JS, Cheng, SH, Meeker, DP, Young, KR, Schoumacher, R, Weatherly, MR, Wing, L, Morris, JE, Sindel, L, Rosenberg, M, Van Ginkel, FW, McGhee, JR, Kelly, D, Lyrene, RK & Sorscher, EJ 2001, 'A clinical inflammatory syndrome attributable to aerosolized lipid-DNA administration in cystic fibrosis', Human Gene Therapy, vol. 12, no. 7, pp. 751-761. https://doi.org/10.1089/104303401750148667
Ruiz, F. E. ; Clancy, J. P. ; Perricone, M. A. ; Bebok, Z. ; Hong, J. S. ; Cheng, S. H. ; Meeker, D. P. ; Young, K. R. ; Schoumacher, Robert ; Weatherly, M. R. ; Wing, L. ; Morris, J. E. ; Sindel, L. ; Rosenberg, M. ; Van Ginkel, F. W. ; McGhee, J. R. ; Kelly, D. ; Lyrene, R. K. ; Sorscher, E. J. / A clinical inflammatory syndrome attributable to aerosolized lipid-DNA administration in cystic fibrosis. In: Human Gene Therapy. 2001 ; Vol. 12, No. 7. pp. 751-761.
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