Nasal gene transfer

Caplen NJ, Alton EW, Middleton PG, Dorin JR, Stevenson BJ, Gao X, Durham SR, Jeffery PK, Hodson ME, Coutelle C (1995) Liposome-mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis. Nat Med 1 39-46... 

Ziady AG, Kelley TJ, Milliken E, Ferkol T, Davis PB (2002) Functional evidence of CFTR gene transfer in nasal epithelium of cystic fibrosis mice in vivo following luminal application of DNA complexes targeted to the serpin-enzyme complex receptor. Mol Ther 5 413-419... 

Answer Aerosol delivery of the CFTR gene. Both viruses and liposome-DNA complexes are capable of successful CFTR gene transfer to the nasal and airway epithelia of patients with CF. In fact, gene transfer to the airways is one of the few areas where liposome-DNA complexes match the expression obtained using viral vectors without the viruses inflammatory side effects. Current trials are aimed at optimizing gene delivery with reduced toxicity to produce sustained correction of the epithelial transport defect. 

Noone, P.G., Hohneker, K.W., Zhou, Z., Johnson, L.G., Foy, C. et al. (2000) Safety and biological efficacy of a lipid-CFTR complex for gene transfer in the nasal epithelium of adult patients with cystic fibrosis. Mol. Then, 1, 105-114. 

Gill, D.R., Southern, K.W., MofFord, K.A., Seddon, T., Huang, L., Sorgi, F. etal. (1997) A placebo-controlled study of liposome-mediated gene transfer to the nasal epithelium of patients with cystic fibrosis. Gene Ther., 4,199-209. 

Porteous, D. J., Dorin, J. R., McLachlan, G., Davidson-Smith, H., Davidson, H., Stevenson, B. J., Carothers, A. D., Wallace, W. A., Moralee, S., Hoenes, C., Kallmeyer, G., Michaelis, U., Naujoks, K., Ho, L. P., Samways, J. M., Imrie, M., Greening, A. P. and Innes, J. A. (1997). Evidence for safety and efficacy of DOTAP cationic liposome mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis. Gene Ther. 4, 210-218. 

Zabner, J., Couture, L. A., Gregory, R. J., Graham, S. M., Smith, A. E. and Welsh, M. J. (1993). Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis. Cell 75, 207-216. 

Kim, T. W., Chung, H., Kwon, I. C., Sung, H. C., and Jeong, S. Y. (2000), In vivo gene transfer to the mouse nasal cavity mucosa using a stable cationic lipid emulsion, Mol. Cells, 10,142-147. 

CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis. Nat. Med. 1(1), 39-16. 

Welsh, M.J., Adenovirus-mediated gene transfer of CFTR to the nasal epithelium and maxiUary sinus of patients with cystic fibrosis. Bethesda, MD, Office of Recombinant DNA Activity, NIH. 

Knowles MR, Hohneker KW, Zhou Z, Olsen JC, Noah TL, Hu P-C, Leigh MW, Engelhardt JF, Edwards LJ, Jones KR, Grossman M, Wilson JM, Johnson LG, Boucher RC. A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis. N Engl J Med 1995 333 823-831. 

Several human and nonhuman model systems have been used to study AAV-mediated gene transfer to the lung (206). A significantnumber ofin vivo studies have been performed in rodents. In these animal models, AAV vector is delivered to the airway epithelium by nasal aspiration or intratracheal instillation (17,207,208). One major problem associated with the use of rodent models is the divergent biology of rodent and human airways from a cellular and anatomical... 

Figure 5 Quantitative analysis of tripeptide proteasome inhibitor Z-LLL on rAAV-2 transduction in mouse lung. 1x10 viral particles of AV2.RSVluciferase virus was delivered into the mouse lung by nasal inhalation. To evaluate the effects of proteasome inhibitor on gene transfer, 400 (jM Z-LLL (final concentration, representing 1% viral inoculation volume) was coadministrated at the time of viral infection. The entire lung was harvested at 8 months postinfection and luciferase activity was evaluated using a previously described protocol (12). The data represents the mean ( SEM) from four independent mice in each group.

Naked or plasmid DNA has also been shown to mediate gene transfer to lung epithelia in vitro and in vivo. In a clinical trial of lipid GL-67 in the nasal epithehum of CF patients, plasmid DNA alone was as effective as GL-67/CETR plasmid DNA lipoplexes, although the restoration of chloride secretion was small in both cases (25). 

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