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For this particular compound, the infiltrates were significant enough to contribute to a decrease in ovarian weight and produce ovarian atrophy. This effect on ovaries was associated with a dose-dependent decrease in the fertility index in mice at doses 20 mg/kg/week. This change was attributed to proinflammatory effects that include an increase in proinflammatory cytokines and chemokines, thus causing the cell infiltrates. Proinflammatory cytokines have been directly associated with ovarian atrophy and the change is therefore considered secondary to the proinflammatory effects rather than an intrinsic toxicity of the oligonucleotide to female reproductive organs [121,122].
Because of the species specificity of the proinflammatory effects discussed earlier, and the doses required to produce these effects (i.e., 20 mg/kg/week), this effect is of little concern to human safety assessment. The other more common observation in fetal development studies is a dose-dependent decrease in maternal body weight and food consumption in female rabbits that is associated with spontaneous abortion and decrease in fetal body weight at the higher dose levels [10,119]. These effects are also associated with the proinflammatory effects of oligonucleotides, and cytokine release has been associated with increases in the rate of abortions [121,122].
Certain of the more potent proinflammatory PS ODNs have been described to have a relatively high rate of abortion. While spontaneous abortions have been observed in rabbits, the incidence is lower for 2 -MOE viagra online compared to first-generation ASO, despite higher target organ concentrations (Table 12.9).
This relative decrease in the reproductive effects of 2 -MOE viagra online in rabbit compared to PS ODNs is consistent with the generally lower degree of proinflammatory effects and further suggests that these effects are not attributable to an intrinsic reproductive toxicity of this class.
There are several examples where investigators have used antisense inhibitors to study the effects on reproduction function. The most notable was the use of a 2 -O-methyl-modified oligonucleotide targeted to vascular endothelial growth factor (VEGF). In this study, antisense treatment produced a 50% inhibition of VEGF mRNA and was associated with developmental abnormalities similar to that observed in the VEGF-deficient mice [123].
These effects were attributed to the inhibition of VEGF both because of the similarity of the phenotype as well as Table 12.9 Comparison of the Relative Dose, Tissue Concentration, Maternal Toxicity, and Fetal Toxicity Correlation between Several Representative PS ODNsand 2 -MOE viagra online ASO Chemistry (mg/kg/week) Kidney Liver (% of control) Frequency Litter Size Alterations aBWbody weight.
To date, oligonucleotide therapeutics are routinely examined in the standard battery of genetic toxicology assays that include the Ames bacterial mutagenicity assay, the CHO cell chromosomal aberrations assay, the L5178Y/TK( /–) mouse lymphoma mammalian gene mutation assay, and the mouse micronucleus assay.
Each of these assays has been performed with 10–12 unique compounds, of which 5–7 have been 2 -MOE ASOs. Less common is the in vitro rat hepatocyte unscheduled DNA synthesis assay. To our knowledge, antisense oligonucleotides have been uniformly negative in these assays with no evidence of mutagenicity or clastogenicity. Representative examples of these assays have been thoroughly reviewed and published for PS ODNs [124].
Importantly, experiments have been performed in parallel for representative compounds to document the exposure of cells to oligonucleotide and the production of metabolites. In vitro assays are performed in the presence and absence of metabolic activation and employ concentrations up to the limit of the assays (5000 g/plate or 5000 g/ml) in the presence and absence of metabolic activation.
The metabolism of oligonucleotide and liberation of the mononucleotide metabolites were among the most significant concerns initially as imbalances in the nucleotide pools have been associated with increased rate of mutations. However, these studies showed that significant accumulation of nucleotides was required to affect the fidelity of DNA repair.
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Obviously, these proinflammatory effects are undesirable for antisense oligonucleotides designed to have other specific pharmacological effects, and so more contemporary viagra online avoid CpG dim...More…
The most relevant question that remains is the chronic renal tolerability of 2 -MOE ASOs. As these second-generation antisense oligonucleotides are only now reaching the later stages of development, ...More…
