title: Secretin-mediated gene delivery, a specific targeting mechanism with potential for treatment of biliary and pancreatic disease in cystic fibrosis.
abstract: Gene therapy directed to the gastroenterological manifestations of cystic fibrosis (CF) would ideally be administered systemically. Such delivery would require efficient targeting at the cellular level to achieve a safe and effective therapy. Here we describe gene delivery using the secretin receptor (SR) as a basolateral target specific to the biliary and pancreatic epithelia affected in CF patients. We describe here targeting of a polycation-based nonviral gene delivery vector and retargeting of an adenoviral vector to cells expressing the SR in vitro. We were able to transfect cells expressing the SR up to 10-fold more efficiently than those not expressing the SR with a targeted polycation, SecGGC-lPEI. This targeting effect was secretin-specific and substantially reduced by competing secretin. SR-retargeted adenovirus transduced SR-expressing cells at more than sixfold higher levels than adenovirus alone. The SR may be an effective target for targeting systemically applied viral and nonviral gene delivery constructs to disease-affected tissues in CF patients.
authors.affiliation: Molecular Genetics, Division of Biomedical Sciences, Sir Alexander Fleming Building, Imperial College School of Medicine, South Kensington, London, SW7 2AZ, UK. t.mckay@icrf.icnet.uk
authors.forename: Tristan
authors.initials: T
authors.lastname: McKay
authors.forename: Paul
authors.initials: P
authors.lastname: Reynolds
authors.forename: Sarah
authors.initials: S
authors.lastname: Jezzard
authors.forename: David
authors.initials: D
authors.lastname: Curiel
authors.forename: Charles
authors.initials: C
authors.lastname: Coutelle
mesh_terms: D000256:Adenoviridae; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D001660:Biliary Tract Diseases / Q000209:etiology / Q000628:therapy*; D016466:CHO Cells; D002213:Capsid / Q000276:immunology; D036022:Capsid Proteins; D006224:Cricetinae; D003550:Cystic Fibrosis / Q000150:complications / Q000628:therapy*; D016503:Drug Delivery Systems; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D010182:Pancreatic Diseases / Q000209:etiology / Q000628:therapy*; D011094:Polyethyleneimine; D051381:Rats; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism*; D012633:Secretin / Q000378:metabolism*; D014162:Transfection
chemical_list: D000914:Antibodies, Viral; D036022:Capsid Proteins; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone; C018315:hexon capsid protein, Adenovirus; C029937:secretin receptor; D012633:Secretin; D011094:Polyethyleneimine