Gene therapy in cystic fibrosis

Flotte TR, Laube BL. Gene therapy in cystic fibrosis. Chest 2001, 120, 124S-131S. 

Yang Y, Nunes FA, Berencsi K, Gonczol E, Engelhard JF, Wilson JM. Inactivation of E2a in recombinant adenoviruses improves the prospect for gene therapy in cystic fibrosis. Nat Genet 1994 7(3) 362-369. 

Although aerosols of various forms for treatment of respiratory disorders have been in use since the middle of the twentieth century, the interest in the use of pulmonary route for systemic drug delivery is recent. Interest in this approach has been further stimulated by the demonstration of potential utility of lung as a portal for entry of peptides and the feasibility of gene therapy for cystic fibrosis. It is important to understand the mechanism of macromolecule absorption by the lungs for an effective use of this route. 

Since the 1980s, hundreds of clinical trials of gene therapy for cystic fibrosis, osteogenesis imperfecta, Gaucher s disease, Fanconi s anemia, and several forms of cancer have been attempted. The problems that need to be overcome in developing a successful strategy for gene therapy are ... 

Gene therapy for cystic fibrosis (CF) has focused on correcting electrolyte transport in aiiway epithelia. Success has been limited by the failure of vectors to attach to and enter into airway epithelia, and may require reduecting vectors to targets on the apical mem-... 

The second delivery method, called in mvo, means that the virus is used to directly infect the patient s tissues. The most common vector for this delivery is the adenoviras (which is a DNA virus). A particular vector can be chosen based on specific receptors on the target tissue. Adenovirus has receptors in lung and liver cells, and it has been used in clinical trials for gene therapy of cystic fibrosis and ornithine transcarbamoylase deficiency. 

Ferrari S, Geddes D M, Alton E W (2002). Barriers to and new approaches for gene therapy and gene delivery in cystic fibrosis. Adv. Drug Deliv. Rev. 54 1373-1393. 

Matsuse T, Teramoto S (2000). Progress in adenovirus-mediated gene therapy for cystic fibrosis lung disease. Curr. Therapeu. Res. 61 422-434. 

Florea, B. L, Thanou, M., Geldof, M. et al. 2000. Modified chitosan oligosaccharides as transfection agents for gene therapy of cystic fibrosis, in Proceedings of 27th International Symposium on Controlled Release of Bioactive Materials, Paris, France Controlled Release Society. 

Lerondel S, Vecellio None L, Faure L, Sizaret PY, Sene C, Pavirani A, Diot P, Le Pape A et al. Gene therapy for cystic fibrosis with aerosolized adenovirus-CFTR characterization of the aerosol and scintigraphic determination of lung deposition in baboons. J Aerosol Med 2001 14(1) 95-105. 

Boucher, R.C. and Knowles, M.R., Gene therapy for cystic fibrosis using El deleted adenovirus a phase I trial in the nasal cavity. Bethesda, MD, Office of Recombinant DNA Activity, NIH. 

The rAAV system was first clinically exploited for gene therapy of cystic fibrosis (CF). A total of four clinical trials of the rAAV-CFTR vector have now been completed. These encompass 70 individuals with CF treated with doses fi-om 6x 10 to 1 x 10 3 Dnase-resistant particles (dip) per administration to the surface of the nose, maxillaiy sinus, or bronchus (21-26). No vector-related adverse effects have been observed. Tiansgene expression has been detected at doses of 6x 10 dip in the sinus or 1 x lO dip in the lung. Phase II trials are ongoing. 

Gene therapy of human genetic disorders is a strategy in which nucleic acid, usually in the form of DNA, is administered to modify the genetic repertoire for therapeutic purposes, as in cystic fibrosis.10... 

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