Toxicological properties of several novel oligonucleotide analogs in mice.
The toxicological properties of ISIS 3082, a phosphorothioate oligonucleotide, and five structurally related analogs of ISIS 3082, were examined in Balb/c mice. Comparisons were made between the uniform phosphorothioate oligonucleotide (ISIS 3082), and a 2' propoxy modified phosphodiester (ISIS 9044), a 2' propoxy phosphorothioate (ISIS 9045), a chimeric oligonucleotide comprised of 2' propoxy diester wings and phosphorothioate deoxy center (ISIS 9046), a 5' C18 amine phosphorothioate (ISIS 9047), or a 5' cholesterol modified phosphorothioate (ISIS 8005) oligonucleotide. Oligonucleotides were administered at 50 mg/kg by i.v. bolus injection (tail vein) every other day for 14 days. In general, the spectrum of alterations observed for ISIS 3082 and all of the analogs were relatively similar. Balb/c mice treated with ISIS 3082 were observed to have increases in liver transaminases and a decrease in triglycerides consistent with results from previous studies performed in CD-1 mice. Spleen weights were also increased in ISIS 3082-treated mice, but no histopathological alterations were noted. ISIS 9046 resulted in a toxicity profile that was very similar to that described for ISIS 3082 with the exception of a slightly lower cholesterol level. Alterations induced by ISIS 9045, ISIS 9047 and ISIS 8005 were qualitatively similar to ISIS 3082, but in general more pronounced, with greater reductions in cholesterol and platelet counts, or increases in blood urea nitrogen relative to ISIS 3082. Red blood cell (RBC) counts and hematocrit were also reduced in mice treated with ISIS 9046, ISIS 9047 and ISIS 8005 relative to the ISIS 3082 treatment group. Kupffer cell hypertrophy and basophilic inclusions in Kupffer cells were observed in mice treated with ISIS 9045, ISIS 9047 and ISIS 8005, but not in ISIS 3082-treated mice. A unique renal lesions was noted in mice treated with ISIS 9044 only that was characterized as mild atrophy of proximal convoluted tubules associated with interstitial fibrosis. With the exception of the renal lesions observed in ISIS 9044 treated mice, the toxicity profiles of various oligonucleotide analogs examined in this study were similar to that observed for ISIS 3082.
Henry
S P
SP
Isis Pharmaceuticals, Inc., Carlsbad, CA 92008, USA.
Zuckerman
J E
JE
Rojko
J
J
Hall
W C
WC
Harman
R J
RJ
Kitchen
D
D
Crooke
S T
ST
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016376:Oligonucleotides, Antisense / Q000633:toxicity*; D010976:Platelet Count / Q000187:drug effects; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D013873:Thionucleotides / Q000633:toxicity*
D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D000410:Alanine Transaminase