Gene Therapy of Submucosal Gland

Cystic fibrosis (CF) has emerged as a paradigm disorder for assessing the utility of gene therapy in the treatment of genetic diseases. It is hypothesized that submucosal glands may play an important role in the pathophysiology of CF lung disease. However, this region poses several significant obstacles for gene therapy due to its inaccessibility from the lumen of adult proximal airways. In utero gene therapy to cor-rect submucosal gland dysfunction in CF provides an attractive alternative strategy to target gland progen-itor cells prior to gland formation and morphogenesis. Such approaches will require the use of integrating vectors capable of transducing expanding stem-cell progenitor-cell populations in the lung. We described a newborn-ferret model of the proximal airway which was used to evaluate the phenotypic characteristics of submucosal gland progenitors and to test gene therapy strategies for targeting these cell types. To this end, we have isolated the ferret cDNA to the lymphoid enhancing factor 1 (Lef1) and have demonstrated that its mRNA expression specifically defines a subset of surface airway epithelial progenitor cells in-volved in the formation of primordial submucosal gland buds and subsequent gland morphogenesis. Suc