title: A second dose of a CFTR cDNA-liposome complex is as effective as the first dose in restoring cAMP-dependent chloride secretion to null CF mice trachea.
abstract: Phase I clinical trials have provided encouraging data suggesting that gene transfer could provide a treatment for cystic fibrosis (CF). However, for all the current viral and nonviral vectors used to deliver the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the duration of CFTR expression is limited, necessitating a repeat dosing regimen to provide a long-term treatment. This study was performed to determine whether a second delivery of a CFTR cDNA-liposome complex could result in a similar level of functional CFTR expression observed after a single delivery and to assess whether the deliveries produced adverse inflammatory responses. CFTR functional expression was assessed by short circuit current measurements of tracheas taken from CF null mice (Cftrtm1Cam) treated with a CFTR cDNA-liposome complex in the upper airways. Mice receiving two deliveries of this complex, the second after the response to the first had declined, showed cAMP-stimulated chloride currents which were not significantly different from normal tracheas or tissues assayed after a single dose of the complex. This double treatment was well tolerated with no discernible inflammation of lung tissue.
authors.affiliation: Physiological Laboratory, University of Cambridge, UK.
authors.forename: C A
authors.initials: CA
authors.lastname: Goddard
authors.forename: R
authors.initials: R
authors.lastname: Ratcliff
authors.forename: J R
authors.initials: JR
authors.lastname: Anderson
authors.forename: E
authors.initials: E
authors.lastname: Glenn
authors.forename: S
authors.initials: S
authors.lastname: Brown
authors.forename: D R
authors.initials: DR
authors.lastname: Gill
authors.forename: S C
authors.initials: SC
authors.lastname: Hyde
authors.forename: L J
authors.initials: LJ
authors.lastname: MacVinish
authors.forename: L
authors.initials: L
authors.lastname: Huang
authors.forename: C F
authors.initials: CF
authors.lastname: Higgins
authors.forename: A W
authors.initials: AW
authors.lastname: Cuthbert
authors.forename: M J
authors.initials: MJ
authors.lastname: Evans
authors.forename: W H
authors.initials: WH
authors.lastname: Colledge
mesh_terms: D000818:Animals; D002412:Cations; D002712:Chlorides / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003550:Cystic Fibrosis / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D018076:DNA, Complementary; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D008081:Liposomes; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological
chemical_list: D002412:Cations; D002712:Chlorides; D018076:DNA, Complementary; D008081:Liposomes; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP