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

Terence R. Flotte, Kevin Sullivan, Randall Wetzel, George Taylor, Barrie J. Carter, William B Guggino, Pamela L. Zeitlin, Thomas C. Reynolds, Alison E. Heald, Patty Pedersen, Suzanne Beck, Carol K. Conrad, Lois Brass-Ernst, Margaret Humphries

Research output: Contribution to journalArticle

Abstract

Recombinant adeno-associated serotype 2-based vectors (rAAV2) possess a number of theoretical advantages for cystic fibrosis (CF) gene therapy because they elicit little or no inflammatory response and generally result in stable expression, rAAV2 vectors expressing the cystic fibrosis transmembrane conductance regulator (CFTR) gene have previously been shown to mediate stable correction of the CF defect in CF bronchial epithelial cells and stable expression of CFTR in rabbit and nonhuman primate models. Here we report the results of the first trial initiated with rAAV in humans, a phase I study in 25 adult and adolescent CF patients with mild to moderate lung disease. Doses of the rAAV-CFTR vector (tgAAVCF) ranging from 3 × 101 to 1 × 109 replication units (RU), which is equivalent to approximately 6 × 104 to 2 × 1012 DNase resistant particles (DRP), were administered to one side of the nose and to the superior segment of the lower lobe of the right lung. Several adverse events were noted prior to and/or after vector delivery, but most of them appeared to be related to the endogenous CF lung disease or a result of the bronchoscopic procedures. Only one of the serious events was judged to be possibly vector-related (based on temporal association), and this event was a pulmonary exacerbation very similar to several others experienced by the same subject in the three months preceding vector delivery. Vector shedding was minimal throughout the study, and serum-neutralizing antibodies were detected after vector delivery to subjects in the highest dosage cohorts. Gene transfer as measured by DNA polymerase chain reaction (PCR) was not observed until cohort 10 in nasal and bronchial epithelia. Sporadic low-level copy numbers suggested gene transfer of anywhere from 0.002 copies per cell up to 0.5 copies per cell was possible; however, DNA PCR was positive in lungs prior to direct dosing suggesting aspiration from the nasal dosing. These data indicate the need for continued evaluation of rAAV-CFTR vectors in additional clinical trials.

Original languageEnglish (US)
Pages (from-to)1079-1088
Number of pages10
JournalHuman Gene Therapy
Volume14
Issue number11
DOIs
StatePublished - Jul 20 2003

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ASJC Scopus subject areas

  • Genetics

Cite this

Flotte, T. R., Sullivan, K., Wetzel, R., Taylor, G., Carter, B. J., Guggino, W. B., Zeitlin, P. L., Reynolds, T. C., Heald, A. E., Pedersen, P., Beck, S., Conrad, C. K., Brass-Ernst, L., & Humphries, M. (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. Human Gene Therapy, 14(11), 1079-1088. https://doi.org/10.1089/104303403322124792