Background Assessing the biological activity and clinical efficacy of gene therapy is critically important in cystic fibrosis (CF). It is widely accepted that clinical testing using surrogate markers including pulmonary function will be useful in assessing clinical efficacy. One problem with pulmonary surrogate markers of CF disease is the large number of patients and length of time required to demonstrate clinical efficacy. An alternative to pulmonary testing of new CF treatments is use of the maxillary sinuses as a surrogate model of CF lung disease. Using CF sinusitis as a surrogate model for testing clinical efficacy of new treatments is attractive because CF upper respiratory disease is similar to the lower respiratory disease with respect to electrophysiology and microbiology. Methods Sinusitis recurrence in untreated sinuses was analyzed during a prospective, randomized, unblinded, dose‐escalation, within‐subjects, phase I clinical trial of the adeno‐associated virus mediated cystic fibrosis transmembrane conductance regulator (AAV‐CFTR) gene transfer. Results Clinical symptoms combined with sinus endoscopy proved useful in the diagnosis of unilateral and bilateral sinusitis recurrence. Sinusitis recurred at a rate of 45% during one month of follow‐up. IL‐8 concentration rose in sinus fluids from affected sinuses. Bacterial cultures and increased sinus leukocytes corroborated recurrent sinusitis. Sinus CT scans were also useful in diagnosing recurrent sinusitis in this surrogate model of CF infectious exacerbations. Conclusions CF sinusitis as a surrogate for lung disease is particularly well‐suited for phase II clinical trials of gene transfer agents, with the potential for measuring clinical efficacy in relatively small numbers of patients over relatively short periods of time. Copyright © 1999 John Wiley & Sons, Ltd.

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