Journal
MOLECULAR THERAPY
Volume 1, Issue 1, Pages 105-114Publisher
ACADEMIC PRESS INC
DOI: 10.1006/mthe.1999.0009
Keywords
liposome; gene transfer; cystic fibrosis; CFTR; EDMPC
Categories
Funding
- NCRR NIH HHS [RR0046] Funding Source: Medline
- PHS HHS [34322] Funding Source: Medline
- NATIONAL CENTER FOR RESEARCH RESOURCES [M01RR000046] Funding Source: NIH RePORTER
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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 ravage 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 Delta CFTR 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.
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