Strategies for non-viral gene delivery to the lungs

Cystic fibrosis, alpha 1-antitrypsin deficiency and surfactant protein B deficiency are examples of lung diseases which could be susceptible to a gene therapy approach. Most gene therapy protocols have used viral vectors for their efficiency of gene transfer. However, all viral vectors induce an immunological response to some degree and have safety risks. Furthermore, their capacity is limited and large scale production may be difficult to achieve. Various non-viral vectors have been developed for gene transfer to the lung. Synthetic vectors are thought to circumvent concerns raised by immunogenicity and safety issues of viral vectors, while offering the potential for repeated administration and large scale production. Cationic polymer PEI has been reported to promote gene transfection into lungs. Cell types transfected with the polymer depend upon various factors like the route of administration and polymer form (branched versus linear). Different startegies for achieving genomic integration of the transgene resulting in long-term expression have also been successfully used. Major drawback of PEI mediated gene delivery is the high cytotoxicity of PEI. Additionally, in vivo application is often limited due to i) colloidal instability in serum as well as high salt concentrations, ii) rapid clearance from the blood stream after systemic application and iii) lack of tissue specificity. To address these problems, biodegradable polymers based on methacrylate have been developed which successfully deliver genes to lung cells and the DNA-polymer complexes, have desireable features of minimal cytotoxicity and enhanced stability in isotonic saline. Various targeting ligands have been coupled to PEI and been shown to not only to enhance gene delivery but also specificity.