**4.2. CF ferret**

CFTR null ferrets were developed using AAV-mediated gene targeting in somatic cells, nuclear transfer, and cloning [95]. Unlike CF mice, CF ferrets develop early and reproducible lung infections that make it a promising platform for testing lung-directed CF therapies [95]. There are several potential reasons for these species differences. First, Ca++-activated Cl channels in the mouse airway may compensate for cAMP-mediated CFTR Cl transport [96, 97], a pathway that appears to be less active in humans or ferrets [95, 98-100]. Second, in humans and ferrets, goblet cells are the predominant secretory cell type of the cartilaginous airways [101-104], whereas in mice the analogous secretory cell type is the club cell [105, 106]. Third, SMGs are virtually absent in murine cartilaginous airways, with only a handful in the most proximal regions of the trachea [106, 107]. SMGs are important for airway innate immunity in the ferret [108] and humans [109, 110], and a potentially valuable site for CFTR expression [111-114].

Lentiviral gene transfer to the wild-type neonatal ferrets using EIAV- and FIV-based vectors expressing fluorescent reporter genes was recently reported [115]. The EIAV was pseudotyped with hemagglutinin (HA) from avian influenza A virus [74] and the FIV vector was pseudo‐ typed with GP64 [63]. A liquid bolus of the vector was delivered to newborn ferrets via a tracheal incision. Significant transgene infection was noted in respiratory epithelia of all lobes in both the conducting and small airways with both vectors. Cmielewski and colleagues delivered VSVG-HIV expressing the LacZ reporter to the lungs of 7—8-week-old ferrets [116]. Considerably less gene transfer was observed as compared to the HA or GP64 pseudotyped LV gene transfer in the neonatal ferrets. Currently, it is unclear if these differences are due to the vector pseudotype, age of the ferrets, or delivery protocol; however, these data suggest that ferrets may be useful pre-clinical models for lentiviral vector development.
