A clinical inflammatory syndrome attributable to aerosolized lipid-DNA administration in cystic fibrosis.
Immunologic reactivity to lipid-DNA conjugates has traditionally been viewed as less of an issue than with viral vectors. We performed a dose escalation safety trial of aerosolized cystic fibrosis transmembrane conductance regulator (CFTR) cDNA to the lower airways of eight adult cystic fibrosis patients, and monitored expression by RT-PCR. The cDNA was complexed to a cationic lipid amphiphile (GL-67) consisting of a cholesterol anchor linked to a spermine head group. CFTR transgene was detected in three patients at 2-7 days after gene administration. Four of the eight patients developed a pronounced clinical syndrome of fever (maximum of 103.3EF), myalgias, and arthralgia beginning within 6 hr of gene administration. Serum IL-6 but not levels of IL-8, IL-1, TNF-alpha, or IFN-gamma became elevated within 1-3 hr of gene administration. No antibodies to the cationic liposome or plasmid DNA were detected. We found that plasmid DNA by itself elicited minimal proliferation of peripheral blood mononuclear cells taken from study patients, but led to brisk immune cell proliferation when complexed to a cationic lipid. Lipid and DNA were synergistic in causing this response. Cellular proliferation was also seen with eukaryotic DNA, suggesting that at least part of the immunologic response to lipid-DNA conjugates is independent of unmethylated (E. coli-derived) CpG sequences that have previously been associated with innate inflammatory changes in the lung.
Ruiz
F E
FE
Gregory Fleming James Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Clancy
J P
JP
Perricone
M A
MA
Bebok
Z
Z
Hong
J S
JS
Cheng
S H
SH
Meeker
D P
DP
Young
K R
KR
Schoumacher
R A
RA
Weatherly
M R
MR
Wing
L
L
Morris
J E
JE
Sindel
L
L
Rosenberg
M
M
van Ginkel
F W
FW
McGhee
J R
JR
Kelly
D
D
Lyrene
R K
RK
Sorscher
E J
EJ
D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000818:Animals; D002412:Cations / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D018899:CpG Islands / Q000235:genetics; D003550:Cystic Fibrosis / Q000235:genetics* / Q000628:therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D004247:DNA / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology / Q000627:therapeutic use; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D008055:Lipids / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D009000:Monocytes / Q000276:immunology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D012137:Respiratory System / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013577:Syndrome; D013997:Time Factors; D019076:Transgenes / Q000235:genetics
C505032:CFTR protein, human; D002412:Cations; D008055:Lipids; D012333:RNA, Messenger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004247:DNA