Pharmaceutical treatments for pulmonary disease may one day include gene transfer therapies for cystic fibrosis (CF), emphysema, oxygen injury, lung cancer, and general inflammatory pulmonary conditions [1]. In 2002, over six hundred clinical trials utilizing gene therapy were completed, ongoing, or pending in 2001, of which roughly 10% targeted lung diseases [2].

A variety of delivery systems and routes of administration have been used for gene delivery to the lung. Viruses are the most common vectors, but lipids and polymeric vectors are gaining in popularity. Routes of administration include: (1) systemic administration, in which the gene carrier may become trapped in the capillary network of the lung; (2) intratracheal (i.t.) instillation of a suspension containing the gene of interest; and (3) inhalation of aerosolized material carrying the therapeutic gene, either as droplets or dry powders. Systemic administration provides direct access to blood vessel endothelial cells, while instillation and inhalation provide direct access to epithelial cells at the air/lung interface. Systemic delivery to the lung may offer a method to bypass the diseased lung yet still reach the target site to achieve a therapeutic result [3,4]. Intratracheal instillation allows for only small doses of material and has a distribution within the lung independent of particle size [5]. It is an invasive technique plagued with low and uneven coverage of lung surfaces [1]. Inhalation requires optimization of inhaler and/or particle characteristics to achieve proper aerosolization and deposition. Deposition within the lung following inhalation is also subject to patient variability [5]. Even so, inhalation of aerosolized material is the most common method of delivery to the respiratory tract, owing to the ease of administration combined with a more uniform distribution [6].

Several important barriers must be overcome before efficient gene therapy in the lung can be realized. A gene entering the lung via inhalation will first encounter the fluid lining the lung surfaces. The innate immunity of the lung surfaces, including an adhesive mucous layer in the upper respiratory tract, surfactant proteins that function specifically in host defense, and alveolar macrophages in the deep lung, provides a formidable barrier to gene delivery. Genes successfully traversing the mucosal barrier encounter cellular barriers that must be overcome before protein translation can occur. Intracellular barriers to gene expression include cellular uptake, endosomal release, nuclear localization, nuclear uptake, and gene transcription, which may require vector/DNA unpacking. Naked DNA has been an inefficient method of gene therapy in the lung, owing to its poor ability to bypass these barriers.

Finally, controlled/targeted deposition of DNA-containing aerosols in various regions of the lung can be achieved by designing aerosols with appropriate physical and chemical attributes. Physical attributes of the particles, such as size, density, and shape, as well as patient-controlled effects, including tidal volume and respiratory rate, significantly affect regional deposition. In addition, proper deaggregation of particles is necessary for predictable and reproducible deposition within the respiratory tract.

This chapter is designed to provide an overview of the important barriers to gene delivery in the lung, but it is not intended as an exhaustive review. We do not attempt to summarize the recent preclinical or clinical aerosol gene therapy literature, nor do we attempt to cover all potential gene carriers. Instead, we were guided by the principle that advances in the basic knowledge related to gene vector design, transport barriers in the lung, and regional targeting should lead to the developing of more efficient carriers for pulmonary gene delivery. For complementary reviews on the topics discussed herein, the reader is referred to Refs. 7-14.

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