Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis

A randomized placebo-controlled phase 2B trial

Richard B. Moss, Carlos Milla, John Louis Colombo, Frank Accurso, Pamela L. Zeitlin, John P. Clancy, L. Terry Spencer, Joseph Pilewski, David A. Waltz, Henry L. Dorkin, Thomas Ferkol, Mark Plan, Bonnie Ramsey, Barrie J. Carter, Dana B. Martin, Alison E. Heald

Research output: Contribution to journalArticle

163 Citations (Scopus)

Abstract

Previous studies have demonstrated that delivery of a recombinant adeno-associated virus (AAV) vector encoding the complete human cystic fibrosis transmembrane regulator (CFTR) cDNA (tgAAVCF) to the nose, sinus, and lungs of subjects with cystic fibrosis (CF) was safe and well tolerated. In a small randomized, double-blind study of three doses of aerosolized tgAAVCF or placebo at 30-day intervals, encouraging but non-significant trends in pulmonary function and induced sputum interleukin 8 (IL-8) levels were seen at early time points. This larger study was conducted to verify these trends. One hundred and two subjects aged 12 years and older with mild-to-moderate cystic fibrosis (forced expiratory flow in 1 sec [FEV1]: 60% predicted) were randomized to two aerosolized doses of 1 × 1013 DNase-resistant particles of tgAAVCF (n = 51) or matching placebo (n = 51) administered 30 days apart. Although tgAAVCF was well tolerated, the study did not meet its primary efficacy end point of statistically significant improvement in FEV1 30 days after initial administration of tgAAVCF compared with placebo. There were no significant differences in spirometric lung function over time, induced sputum biologic markers, or days of antibiotic use in either treatment group. Thus repeated doses of aerosolized tgAAVCF were safe and well tolerated, but did not result in significant improvement in lung function over time. Because gene transfer is the simplest, most basic way to correct the underlying genetic defect that leads to disease in CF, further research is warranted to develop an effective gene transfer agent for the treatment of CF.

Original languageEnglish (US)
Pages (from-to)726-732
Number of pages7
JournalHuman gene therapy
Volume18
Issue number8
DOIs
StatePublished - Aug 1 2007

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Dependovirus
Cystic Fibrosis
Placebos
Lung
Sputum
Therapeutics
Deoxyribonucleases
Interleukin-8
Nose
Double-Blind Method
Genes
Complementary DNA
Biomarkers
Anti-Bacterial Agents
Research

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis : A randomized placebo-controlled phase 2B trial. / Moss, Richard B.; Milla, Carlos; Colombo, John Louis; Accurso, Frank; Zeitlin, Pamela L.; Clancy, John P.; Spencer, L. Terry; Pilewski, Joseph; Waltz, David A.; Dorkin, Henry L.; Ferkol, Thomas; Plan, Mark; Ramsey, Bonnie; Carter, Barrie J.; Martin, Dana B.; Heald, Alison E.

In: Human gene therapy, Vol. 18, No. 8, 01.08.2007, p. 726-732.

Research output: Contribution to journalArticle

Moss, RB, Milla, C, Colombo, JL, Accurso, F, Zeitlin, PL, Clancy, JP, Spencer, LT, Pilewski, J, Waltz, DA, Dorkin, HL, Ferkol, T, Plan, M, Ramsey, B, Carter, BJ, Martin, DB & Heald, AE 2007, 'Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis: A randomized placebo-controlled phase 2B trial', Human gene therapy, vol. 18, no. 8, pp. 726-732. https://doi.org/10.1089/hum.2007.022
Moss, Richard B. ; Milla, Carlos ; Colombo, John Louis ; Accurso, Frank ; Zeitlin, Pamela L. ; Clancy, John P. ; Spencer, L. Terry ; Pilewski, Joseph ; Waltz, David A. ; Dorkin, Henry L. ; Ferkol, Thomas ; Plan, Mark ; Ramsey, Bonnie ; Carter, Barrie J. ; Martin, Dana B. ; Heald, Alison E. / Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis : A randomized placebo-controlled phase 2B trial. In: Human gene therapy. 2007 ; Vol. 18, No. 8. pp. 726-732.
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