Oligonucleotide therapeutics

H. E. Moser, Stategies and Chemical Approaches towards Oligonucleotide Therapeutics , in Perspectives in Medicinal Chemistry , Eds. B. Testa, E. Kyburz, W. Fuhrer, and R. Giger, Verlag Helvetica Chimica Acta, Basel, 1993, p. 275 - 297. 

Gewirtz, A.M. (1997) Oligonucleotide therapeutics for human leukaemia. In D.J.Chadwick and G.Cardew (eds) Oligonucleotides as Therapeutic Agents. Ciba Foundation Symposium 209, Wiley, Chichester, pp. 169-194. 

Gewirtz, A.M. (2000) Oligonucleotide therapeutics a step forward. J. Clin. Oncol., 18, 1809-1811. 

Toxicology of Oligonucleotide Therapeutics and Understanding the Relevance of the Toxicities... 

This chapter will describe the existing practices for assessing the toxicity of oligonucleotide therapeutics and the rationale for these practices. The only... 

One strategy being used for a full assessment of the pharmaco/toxicokinet-ics of oligonucleotide therapeutics is to perform a mass balance study with... 

When trying to understand the toxicity of oligonucleotide therapeutics, it is useful to classify the sources of toxicity. An oligonucleotide therapeutic can produce toxicity either through a hybridization-dependent or hybridization-independent mechanism. 

Assessing the Genotoxicity Most of the published data on the genotoxicity of oligonucleotide therapeutic agents is for the PS ODNs. PS ODNs have... 

Genotoxic Potential of Oligonucleotide Therapeutics Published data from genotoxicity assays for a number of different PS ODNs indicate that there is little or no genotoxic potential. Additionally ISIS has tested more than 10 unique sequences, all routinely negative (Table 24.1). 

Assessing the Safety Pharmacology of Oligonucleotide Therapeutic Agents The battery of safety pharmacology studies for oligonucleotide compounds can be ascertained from the ICFI guidance on the topic. 

There are other complex issues with regard to the assessment of safety pharmacology studies. With the oligonucleotide therapeutics that modulate the translation of mRNA to proteins, like antisense/siRNA, there is a lag between administration of the drug and the pharmacologic activity that is mediated by reduction in protein levels. This lag is related to the mechanism of action and how long it takes for a reduction in protein synthesis to be reflected in reduced protein levels. Because of this lag it is probably better to... 

Cardiovascular Safety Effects on vascular tone have received the most attention, as a result of toxicities that were identified very early in the development of the first systemically administered PS ODNs. We showed that there was correlation between complement activation and the reported alterations in blood pressure and heart rate in monkeys treated with high doses of PS ODN [40-42], The observation appears to be unique or at least more prominent in monkeys, and that has actually driven the need to characterize the toxicity of oligonucleotide therapeutics in monkeys as the nonrodent species. (Note that complement activation has not proved to be a significant issue in the clinic, although in clinical studies we strive to avoid plasma levels that might be associated anaphylactoid responses in monkeys.)... 

Oligonucleotide therapeutics have a relatively low order of acute toxicity, with the notable exception of the polyanionic PS ODNs, which have been known to activate complement through the alternative pathway in monkeys. Because these compounds do not cross the blood-brain barrier nor accumulate in cardiac muscle, and because the uptake of these compounds is dependent on saturable processes, very high doses of oligonucleotides tend not to produce central effects or acute organ failure, thus lowering the potential for acute lethality. 

Some oligonucleotide therapeutics (aptamers) have been designed specifically to inhibit clotting, and for those compounds the anticoagulant effects are more pronounced, as intended. The doses used in toxicity studies are designed to characterize the superpharmacology of these agents. 

The most obvious effect on the immune system with oligonucleotide administration is the tendency to stimulate a pro-inflammatory reaction in some species (reviewed in [31,74]). Whether this is a true immunotoxicity is one of the questions that needs to be addressed for oligonucleotide therapeutics. 

---