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
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.