Comprehensive analysis of the acute toxicities induced by systemic administration of cationic lipid: Plasmid DNA complexes in mice

Citation
Jd. Tousignant et al., Comprehensive analysis of the acute toxicities induced by systemic administration of cationic lipid: Plasmid DNA complexes in mice, HUM GENE TH, 11(18), 2000, pp. 2493-2513
Citations number
74
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Molecular Biology & Genetics
Journal title
HUMAN GENE THERAPY
ISSN journal
1043-0342 → ACNP
Volume
11
Issue
18
Year of publication
2000
Pages
2493 - 2513
Database
ISI
SICI code
1043-0342(200012)11:18<2493:CAOTAT>2.0.ZU;2-0
Abstract
A major limitation associated with systemic administration of cationic lipi d: plasmid DNA (pDNA) complexes is the vector toxicity at the doses necessa ry to produce therapeutically relevant levels of transgene expression. Syst ematic evaluation of these toxicities has revealed that mice injected intra venously with cationic lipid: pDNA complexes develop significant, dose-depe ndent hematologic and serologic changes typified by profound leukopenia, th rombocytopenia, and elevated levels of serum transaminases indicative of he patocellular necrosis. Vector administration also induced a potent inflamma tory response characterized by complement activation and the induction of t he cytokines IFN-gamma, TNF-alpha, IL-6, and IL-12. These toxicities were f ound to be transient, resolving with different kinetics to pretreatment lev els by 14 days posttreatment. The toxic syndrome observed was independent o f the cationic lipid: pDNA ratio, the cationic lipid species, and the level of transgene expression attained. Mechanistic studies determined that neit her the complement cascade nor TNF-alpha were key mediators in the developm ent of these characteristic toxicities. Administration of equivalent doses of the individual vector components revealed that cationic liposomes or pDN A alone did not generate the toxic responses observed with cationic lipid: pDNA complexes. Only moderate leukopenia was associated with administration of cationic liposomes or pDNA alone, while only mild thrombocytopenia was noted in pDNA-treated animals. These results establish a panel of objective parameters that can be used to quantify the acute toxicities resulting fro m systemic administration of cationic lipid: pDNA complexes, which in turn provides a means to compare the therapeutic indices of these vectors.