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Targeting expression of a transgene to the airway surface epithelium using a ciliated cell-specific promoter.

Ostrowski LE, Hutchins JR, Zakel K, O'Neal WK
Molecular therapy : the journal of the American Society of Gene Therapy


Many of the vectors being investigated for gene therapy utilize viral promoters or promoters from ubiquitously expressed genes (e.g., CMV, beta-actin). These promoters are active in many cell types and generally result in high levels of transgene expression. However, the use of these promoters for gene therapy of cystic fibrosis (CF) may produce undesirable effects by directing high levels of CFTR expression in cells that normally do not synthesize this protein. In contrast, a vector containing a ciliated cell-specific promoter and delivered to the lung would be active only in the ciliated cells that line the surface of the airways. Ciliated cells express CFTR and are in direct contact with the airway surface liquid normally regulated by CFTR. To develop a ciliated cell-specific promoter for CF gene therapy, we have characterized the promoter region of the FOXJ1 gene, a transcription factor required for ciliated cell differentiation. A fragment of the human FOXJ1 promoter region was inserted into an EGFP expression cassette and used to produce transgenic mice. Transgene-positive animals demonstrated strong EGFP expression in the ciliated cells of tracheal, bronchial, and nasal epithelium. Our results demonstrate that elements within the FOXJ1 promoter region are sufficient to target expression of transgenes to ciliated cells and may be useful for gene therapy of CF.

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