Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression
ReviewA review of issues in the pharmacokinetics and toxicology of phosphorothioate antisense oligonucleotides
Introduction
The development of antisense compounds as therapeutic agents is moving forward rapidly. The recent FDA approval of Vitravene (fomivirsen sodium) highlights the progress made in moving antisense oligonucleotides from the laboratory to the market place. Questions continually arise regarding the toxicity and pharmacokinetics of these novel therapeutic agents. This review will address some of the major areas of concern. Because most of the toxicology and pharmacokinetic data were generated with phosphorothioate oligonucleotides, this review will therefore concentrate on that class of antisense oligonucleotides. Sequences of all oligonucleotides referenced in this article are included in Table 1.
Section snippets
Currently employed methods to deliver phosphorothioate oligonucleotides
The initial clinical trials with oligonucleotides used local injections to achieve therapeutic concentrations at or near the disease site. For example, the first clinical trials of an antisense oligonucleotide were performed with intradermal injections of ISIS 2105 at the site of genital warts. ISIS 2105 is an agent targeting the translation start codon of the E2 mRNA of human papilloma viruses (HPV-6, HPV-11). Local concentrations of oligonucleotide at the site of injection were relatively
Toxicity issues
Toxicity from antisense oligonucleotides can be induced by hybridization-dependent and hybridization-independent mechanisms. Major issues in characterizing the toxicity of antisense compounds are to differentiate between the hybridization-dependent and -independent toxicity and how to insure that there are no inappropriate hybridization events. Careful analysis of the existing data provides insight into these issues. The toxicities observed in preclinical toxicity studies all appear to be
Reproductive effects of antisense oligodeoxynucleotides
Antisense compounds have shown activity in in vitro models of embryonic development and have been used to study the effects of altering gene transcription on morphogenesis. Sadler [89], [90] used antisense oligodeoxynucleotides as a tool to knockout the expression of a specific gene product, Engrailed-1 (En-1), in cultured mouse embryos. These experiments demonstrated that sequence-dependent alterations in developing mice embryos could be produced by a single intra-yolk sac injection of 15–25
Conclusion
There is a growing body of data characterizing the toxicity and pharmacokinetics of antisense oligonucleotides. These data demonstrate that these compounds can be safely administered and that the drugs themselves reach a broad range of target tissues. We continue to add to our understanding of this molecules as we move towards even more potent and more durable antisense compounds.
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