Coarse spray delivery to a localized region of the pulmonary airways for gene therapy

Targeting adenoviral vectors for cystic fibrosis gene therapy to the human airways with minimal exposure to alveoli would avoid adverse reactions and maximize response. At present, to deliver gene therapy vectors, large volum es of fluid are instilled or nebulized as aerosols, Either approach would l ikely cause alveolar exposure and increases the potential for side effects. We describe a coarse spray delivery device that precisely and reproducibly delivers the viral vector to the human airways to treat a small region of the airways for clinical trials, An endoscopic washing pipe (Olympus) that can be inserted into the channel of a bronchoscope was used, To minimize th e escape of the therapeutic material downstream from the site of administra tion, we restricted the volume delivered to <150 mu l (to prevent bulk flow ), and used large droplets. Their high velocity further enhanced the probab ility of impaction in the vicinity of the nozzle. A pneumatic dosing system (Kahnetics) was used to reproducibly deliver the spray. The droplet size d istribution was determined by laser diffraction and confirmed by cascade im paction: 190-mu m volume median diameter with 1% mass <10 mu m. The localiz ation of the spr ay was studied in hollow cast models of human airways. Tc- 99m-sulfur colloid was used as a radiolabeled marker for these studies. Loc alization of the deposited spray was determined by scintigraphy and by meas uring the radioactivity exiting the terminal airways. In the lung casts the spray was localized to one or two generations over an similar to 2-cm(2) a rea. We conclude that delivery of large droplet sprays limits exposure to a few generations and may be useful in topical gene delivery clinical trials .