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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, the data to answer this question are not mature enough to make broad conclusions. We have completed 6 months of treatment for a representative oligonucleotide in this class, ISIS 141923. In this study, monkeys were treated with ISIS 141923 by once-weekly administration of 20 mg/kg/week for 26 weeks.
As expected, the target organ effect at this dose level was in kidney and correlated with the highest tissue concentration. As discussed above, the kidney cortex concentration achieved steady state concentration by 4–6 weeks and was maintained through the treatment duration for this dose level.
Importantly, the histologic changes observed after chronic treatment were similar to those observed after subchronic duration of treatment, suggesting no progression of toxicity in monkeys at least with up to 6 months of treatment (Table 12.8). There were also no changes in markers of renal function in either serum or urine. No other significant changes were noted in body weight, clinical pathology, organ weight, or histopathology. For sure, more data are needed to address this issue and more data will be forthcoming. However, present data begin to address the chronic tolerability of 2 -MOE ASOs.
Reproductive toxicity of PS ODNs and now several 2 -MOE viagra online have been evaluated in male and female mice and in rabbits, examining the effects of fertility, fetal development, and development and reproductive function of offspring. Oligonucleotide effects on reproductive organs are limited, in part because of the very low degree of oligonucleotide exposure, particularly to male reproductive organs or developing fetus.
For example, the oligonucleotide concentrations in testes is typically among the lowest of any of the organs examined, and immunohistochemical examination indicates that what oligonucleotide is present does not cross the blood-testes barrier, but instead is contained in interstitial tissue macrophages. This is important, as it reduces concern for exposure of the germ line cells to oligonucleotides.
No effect on testes morphology or male reproductive function has been observed for any oligonucleotide studied to date [118,119]. In pregnant females, very little oligonucleotide is associated with placenta and the concentrations of oligonucleotide in fetal kidney or liver are typically below the level of quantitation [118,119].
This indicates that very little oligonucleotide is transferred across the placenta. Detailed analysis of distribution to placenta has indicated that oligonucleotide concentrations are higher on the maternal side of the placenta in rats, documenting the distribution to fetus, and quantifying that fetal kidney concentrations are 1% of those measured in maternal kidney [120].
This limited fetal exposure to oligonucleotide greatly decreases the concerns for fetal development. Reproductive organs that have been a target for toxicity in rodents include ovaries, uterus, and vagina. Oligonucleotide is distributed to ovaries and uterus, and in mice there has been observation of dose-dependent increase in lymphohistiocytic cell infiltrates in these tissues associated with the proinflammatory effects so commonly observed in this species. In our experience, however, there has only been one case where this exposure to oligonucleotide and increase in cell infiltrate was correlated with a functional change in mice. The 2 -MOE ASO inhibitor of TNFproduced a particular marked level of cell infiltrates in mice at doses 35 mg/kg/week.
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