Chest
Clinical InvestigationsAEROSOLSRepeated 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
Section snippets
Study Agent
Active study agent was tgAAVCF, a recombinant AAV2 vector genetically engineered to contain the complete coding region of the human CFTR cDNA. The vector was constructed by replacing the entire wild-type AAV viral coding sequence with the full-length human CFTR cDNA and a synthetic polyadenylation sequence based on murine β-globulin. This construct was flanked by the AAV2 inverted terminal repeat sequences that are required for viral replication and packaging during the manufacturing process.
Baseline Characteristics
Forty-six subjects underwent screening procedures between October 2000 and April 2002. Four subjects did not meet entry criteria because the baseline FEV1 was ≤ 60% of predicted. Forty-two subjects were randomized. After the first two subjects were randomized, the FDA imposed a 2-month hold in December 2000 on all clinical trials involving any AAV vector to review findings from an animal study of a vector unrelated to tgAAVCF.3031 The first subject, who had received one dose of study
Discussion
This study represents the first clinical evaluation of repeated aerosol dose delivery of CFTR DNA to the lower respiratory tract of patients with CF using an AAV vector. The study was designed with safety and tolerability as the primary end points. Thus, the trial was powered and sample size calculated to detect differences in adverse events between subjects receiving tgAAVCF and placebo. The reason for this emphasis on safety lies in clinical toxicity encountered in previous attempts to
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Supported by the Cystic Fibrosis Foundation, the General Clinical Research Centers Program, NCRR, Targeted Genetics Corporation, the Ross Mosier Fund, and the Berger-Raynolds Fund.
Dr. Heald is an employee of Targeted Genetics Corporation, manufacturer of the gene vector used in this study.