TOXICOLOGICAL PROPERTIES OF SEVERAL NOVEL OLIGONUCLEOTIDE ANALOGS IN MICE

The toxicological properties of ISIS 3082, a phosphorothioate oligonuc leotide, and five structurally related analogs of ISIS 3082, were exam ined in Balb/c mice. Comparisons were made between the uniform phospho rothioate oligonucleotide (ISIS 3082), and a 2' propoxy modified phosp hodiester (ISIS 9044), a 2' propoxy phosphorothioate (ISIS 9045), a ch imeric oligonucleotide comprised of 2' propoxy diester wings and phosp horothioate 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 an alogs were relatively similar. Balb/c mice treated with ISIS 3082 were observed to have increases in liver transaminases and a decrease in t riglycerides consistent with results from previous studies performed i n CD-1 mice. Spleen weights were also increased in ISIS 3082-treated m ice, but no histopathological alterations were noted. ISIS 9046 result ed in a toxicity profile that was very similar to that described for I SIS 3082 with the exception of a slightly lower cholesterol level. Alt erations induced by ISIS 9045, ISIS 9047 and ISIS 8005 were qualitativ ely 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 h ematocrit 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 i n mice treated with ISIS 9045, ISIS 9047 and ISIS 8005, but not in ISI S 3082-treated mice. A unique renal lesion was noted in mice treated w ith ISIS 9044 only that was characterized as mild atrophy of proximal convoluted tubules associated with interstitial fibrosis. With the exc eption of the renal lesion observed in ISIS 9044 treated mice, the tox icity profiles of various oligonucleotide analogs examined in this stu dy were similar to that observed for ISIS 3082.