Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus

Ben Gary Harvey, Philip L. Leopold, Neil R. Hackett, Tina M. Grasso, P. Mickey Williams, Ayly L. Tucker, Robert J. Kaner, Barbara Ferris, Igor Gonda, Theresa D. Sweeney, Ramachandran Ramalingam, Imre Kovesdi, Steven Shak, Ronald Crystal

Research output: Contribution to journalArticle

189 Citations (Scopus)

Abstract

We sought to evaluate the ability of an E1-, E3- adenovirus (Ad) vector (Ad(GV)CFTR.10) to transfer the normal human cystic fibrosis transmembrane conductance regulator (CFTR) cDNA to the airway epithelium of individuals with cystic fibrosis (CF). We administered Ad(GV)CFTR.10 at doses of 3 x 106 to 2 x 109 plaque-forming units over 9 months by endobronchial spray to 7 pairs of individuals with CF. Each 3-month cycle, we measured vector-derived versus endogenous CFTR mRNA in airway epithelial cells prior to therapy, as well as 3 and 30 days after therapy. The data demonstrate that (a) this strategy appears to be safe; (b) after the first administration, vector-derived CFTR cDNA expression in the CF airway epithelium is dose- dependent, with greater than 5% endogenous CFTR mRNA levels at the higher vector doses; (c) expression is transient, lasting less than 30 days; (d) expression can be achieved with a second administration, but only at intermediate doses, and no expression is observed with the third administration; and (e) the progressive lack of expression with repetitive administration does not closely correlate with induction of systemic anti-Ad neutralizing antibodies. The major advantage of an Ad vector is that it can deliver sufficient levels of CFTR cDNA to the airway epithelium so that CFTR expression protects the lungs from the respiratory manifestations of CF. However, this impressive level of expression is linked to the challenging fact that expression is limited in time. Although this can be initially overcome by repetitive administration, unknown mechanisms eventually limit this strategy, and further repetitive administration does not lead to repetitive expression.

Original languageEnglish
Pages (from-to)1245-1255
Number of pages11
JournalJournal of Clinical Investigation
Volume104
Issue number9
DOIs
Publication statusPublished - 1 Jan 1999
Externally publishedYes

Fingerprint

Cystic Fibrosis Transmembrane Conductance Regulator
Adenoviridae
Cystic Fibrosis
Messenger RNA
Epithelium
Complementary DNA
Neutralizing Antibodies
Epithelial Cells
Lung
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus. / Harvey, Ben Gary; Leopold, Philip L.; Hackett, Neil R.; Grasso, Tina M.; Williams, P. Mickey; Tucker, Ayly L.; Kaner, Robert J.; Ferris, Barbara; Gonda, Igor; Sweeney, Theresa D.; Ramalingam, Ramachandran; Kovesdi, Imre; Shak, Steven; Crystal, Ronald.

In: Journal of Clinical Investigation, Vol. 104, No. 9, 01.01.1999, p. 1245-1255.

Research output: Contribution to journalArticle

Harvey, BG, Leopold, PL, Hackett, NR, Grasso, TM, Williams, PM, Tucker, AL, Kaner, RJ, Ferris, B, Gonda, I, Sweeney, TD, Ramalingam, R, Kovesdi, I, Shak, S & Crystal, R 1999, 'Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus', Journal of Clinical Investigation, vol. 104, no. 9, pp. 1245-1255. https://doi.org/10.1172/JCI7935
Harvey, Ben Gary ; Leopold, Philip L. ; Hackett, Neil R. ; Grasso, Tina M. ; Williams, P. Mickey ; Tucker, Ayly L. ; Kaner, Robert J. ; Ferris, Barbara ; Gonda, Igor ; Sweeney, Theresa D. ; Ramalingam, Ramachandran ; Kovesdi, Imre ; Shak, Steven ; Crystal, Ronald. / Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus. In: Journal of Clinical Investigation. 1999 ; Vol. 104, No. 9. pp. 1245-1255.
@article{6645155e42c34a2cb06a3f3edb74393e,
title = "Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus",
abstract = "We sought to evaluate the ability of an E1-, E3- adenovirus (Ad) vector (Ad(GV)CFTR.10) to transfer the normal human cystic fibrosis transmembrane conductance regulator (CFTR) cDNA to the airway epithelium of individuals with cystic fibrosis (CF). We administered Ad(GV)CFTR.10 at doses of 3 x 106 to 2 x 109 plaque-forming units over 9 months by endobronchial spray to 7 pairs of individuals with CF. Each 3-month cycle, we measured vector-derived versus endogenous CFTR mRNA in airway epithelial cells prior to therapy, as well as 3 and 30 days after therapy. The data demonstrate that (a) this strategy appears to be safe; (b) after the first administration, vector-derived CFTR cDNA expression in the CF airway epithelium is dose- dependent, with greater than 5{\%} endogenous CFTR mRNA levels at the higher vector doses; (c) expression is transient, lasting less than 30 days; (d) expression can be achieved with a second administration, but only at intermediate doses, and no expression is observed with the third administration; and (e) the progressive lack of expression with repetitive administration does not closely correlate with induction of systemic anti-Ad neutralizing antibodies. The major advantage of an Ad vector is that it can deliver sufficient levels of CFTR cDNA to the airway epithelium so that CFTR expression protects the lungs from the respiratory manifestations of CF. However, this impressive level of expression is linked to the challenging fact that expression is limited in time. Although this can be initially overcome by repetitive administration, unknown mechanisms eventually limit this strategy, and further repetitive administration does not lead to repetitive expression.",
author = "Harvey, {Ben Gary} and Leopold, {Philip L.} and Hackett, {Neil R.} and Grasso, {Tina M.} and Williams, {P. Mickey} and Tucker, {Ayly L.} and Kaner, {Robert J.} and Barbara Ferris and Igor Gonda and Sweeney, {Theresa D.} and Ramachandran Ramalingam and Imre Kovesdi and Steven Shak and Ronald Crystal",
year = "1999",
month = "1",
day = "1",
doi = "10.1172/JCI7935",
language = "English",
volume = "104",
pages = "1245--1255",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "9",

}

TY - JOUR

T1 - Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus

AU - Harvey, Ben Gary

AU - Leopold, Philip L.

AU - Hackett, Neil R.

AU - Grasso, Tina M.

AU - Williams, P. Mickey

AU - Tucker, Ayly L.

AU - Kaner, Robert J.

AU - Ferris, Barbara

AU - Gonda, Igor

AU - Sweeney, Theresa D.

AU - Ramalingam, Ramachandran

AU - Kovesdi, Imre

AU - Shak, Steven

AU - Crystal, Ronald

PY - 1999/1/1

Y1 - 1999/1/1

N2 - We sought to evaluate the ability of an E1-, E3- adenovirus (Ad) vector (Ad(GV)CFTR.10) to transfer the normal human cystic fibrosis transmembrane conductance regulator (CFTR) cDNA to the airway epithelium of individuals with cystic fibrosis (CF). We administered Ad(GV)CFTR.10 at doses of 3 x 106 to 2 x 109 plaque-forming units over 9 months by endobronchial spray to 7 pairs of individuals with CF. Each 3-month cycle, we measured vector-derived versus endogenous CFTR mRNA in airway epithelial cells prior to therapy, as well as 3 and 30 days after therapy. The data demonstrate that (a) this strategy appears to be safe; (b) after the first administration, vector-derived CFTR cDNA expression in the CF airway epithelium is dose- dependent, with greater than 5% endogenous CFTR mRNA levels at the higher vector doses; (c) expression is transient, lasting less than 30 days; (d) expression can be achieved with a second administration, but only at intermediate doses, and no expression is observed with the third administration; and (e) the progressive lack of expression with repetitive administration does not closely correlate with induction of systemic anti-Ad neutralizing antibodies. The major advantage of an Ad vector is that it can deliver sufficient levels of CFTR cDNA to the airway epithelium so that CFTR expression protects the lungs from the respiratory manifestations of CF. However, this impressive level of expression is linked to the challenging fact that expression is limited in time. Although this can be initially overcome by repetitive administration, unknown mechanisms eventually limit this strategy, and further repetitive administration does not lead to repetitive expression.

AB - We sought to evaluate the ability of an E1-, E3- adenovirus (Ad) vector (Ad(GV)CFTR.10) to transfer the normal human cystic fibrosis transmembrane conductance regulator (CFTR) cDNA to the airway epithelium of individuals with cystic fibrosis (CF). We administered Ad(GV)CFTR.10 at doses of 3 x 106 to 2 x 109 plaque-forming units over 9 months by endobronchial spray to 7 pairs of individuals with CF. Each 3-month cycle, we measured vector-derived versus endogenous CFTR mRNA in airway epithelial cells prior to therapy, as well as 3 and 30 days after therapy. The data demonstrate that (a) this strategy appears to be safe; (b) after the first administration, vector-derived CFTR cDNA expression in the CF airway epithelium is dose- dependent, with greater than 5% endogenous CFTR mRNA levels at the higher vector doses; (c) expression is transient, lasting less than 30 days; (d) expression can be achieved with a second administration, but only at intermediate doses, and no expression is observed with the third administration; and (e) the progressive lack of expression with repetitive administration does not closely correlate with induction of systemic anti-Ad neutralizing antibodies. The major advantage of an Ad vector is that it can deliver sufficient levels of CFTR cDNA to the airway epithelium so that CFTR expression protects the lungs from the respiratory manifestations of CF. However, this impressive level of expression is linked to the challenging fact that expression is limited in time. Although this can be initially overcome by repetitive administration, unknown mechanisms eventually limit this strategy, and further repetitive administration does not lead to repetitive expression.

UR - http://www.scopus.com/inward/record.url?scp=0032718592&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032718592&partnerID=8YFLogxK

U2 - 10.1172/JCI7935

DO - 10.1172/JCI7935

M3 - Article

C2 - 10545523

AN - SCOPUS:0032718592

VL - 104

SP - 1245

EP - 1255

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 9

ER -