IMMUNOSUPPRESSION & ADENOVIRAL MEDIATED GENE TRANSFER: CYSTIC FIBROSIS

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The genetic mutation in cystic fibrosis (CF) affects the expression of a regulator of cellular ion transport (CFTR). The primary manifestations of this defect occur in the lung, liver, and pancreas. Phase-I clinical trials of CF-gene replacement, using adenoviral vectors (AdV) which are known to efficiently deliver genes to the lung and liver, have had limited success because host responses to the AdV reduce the duration of transgenic expression of CFTR. Prior studies in a murine model show that CD4+ lymphocytes are critical to these responses to the AdV, in that injection of a depleting anti-CD4 antibody results in prolonged transgene expression in AdV's targeting the liver and that injection on a non-depleting anti-CD4 antibody prolongs AdV-mediated expression of a reporter gene in the lungs. Promising results have also been obtained in delivery of a liver-targeted gene in an immunosuppressed primate model. Based on these findings, we hypothesize that the ability of AdV to deliver CFTR to the lung can be extended by transient suppression of the natural cytotoxic-T-cell and antibody-neutralizing B-cell responses to AdV using anti-CD4 antibody treatment. The aims of this project are to test specific predictions of this hypothesis are 1) investigate the effect of OKT4a (a non-depleting anti-CD4 antibody) on duration of reporter gene expression and anti-adenovirus antibody production in the primate lung; 2) investigate the effect of OKT4a on the ability to re-administer and express a second reporter gene. The results will have direct