Safety and biological efficacy of a lipid-CFTR complex for gene transfer in the nasal epithelium of adult patients with cystic fibrosis.
Gene transfer is an attractive option to treat the basic defect in cystic fibrosis. In a double-blind, placebo-controlled, rising-dose tolerance study in the nasal epithelium, we tested the safety and efficacy of a cationic liposome [p-ethyl-dimyristoylphosphadityl choline (EDMPC) cholesterol] complexed with an expression plasmid containing hCFTR cDNA. Eleven adult CF patients were studied in a protocol that allowed comparisons within individual subjects: vector and placebo were sprayed into alternate nostrils at intervals over 7 h. After dosing, vector-specific DNA was present in nasal lavage of all subjects for up to 10 days. There were no adverse events. The vector-treated epithelium did not exhibit a significant increase in CFTR-mediated Cl- conductance from baseline and was not different from the placebo-treated nostril: mean deltaCFTR Cl- conductance, mV +/- SEM, -1.6+/-0.4 vs -0.6+/-0.4, respectively. CFTR-mediated Cl- conductance increased toward normal during repetitive nasal potential difference measurements over the 3 days before dosing which influenced the postdosing calculations. No vector-specific mRNA was detected in the nasal epithelial scrape biopsies, although endogenous CFTR mRNA was detected in all subjects. We conclude that the lipid-DNA complex is safe, but did not produce consistent evidence of gene transfer to the nasal epithelium by physiologic or molecular measures.
The Cystic Fibrosis/Pulmonary Research and Treatment Center, Division of Pulmonary Medicine, University of North Carolina at Chapel Hill, 27599, USA. pnoone@med.unc.edu
P G
PG
Noone
K W
KW
Hohneker
Z
Z
Zhou
L G
LG
Johnson
C
C
Foy
C
C
Gipson
K
K
Jones
T L
TL
Noah
M W
MW
Leigh
C
C
Schwartzbach
J
J
Efthimiou
R
R
Pearlman
R C
RC
Boucher
M R
MR
Knowles
D000328:Adult; D001483:Base Sequence; D002712:Chlorides / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000008:administration & dosage / Q000235:genetics; D004311:Double-Blind Method; D004553:Electric Conductivity; D004848:Epithelium / Q000378:metabolism; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D009297:Nasal Mucosa / Q000378:metabolism; D012449:Safety
C505032:CFTR protein, human; D002712:Chlorides; D017931:DNA Primers; D018076:DNA, Complementary; D008081:Liposomes; D019005:Cystic Fibrosis Transmembrane Conductance Regulator