As is to be expected with first-generation technology, undesirable properties have been identified for phosphorothioate oligodeoxynucleotides (149,150,314,315). Despite these limitations, it is possible to use phosphorothioate oligodeoxynu-cleotides to selectively inhibit the expression of a targeted RNA in cell culture and in vivo. The pharmacokinetics of phosphorothioate oligodeoxynucleotides are similar across species and do not appear to exhibit major sequence-specific differences. When dosed at high levels, it is possible to identify toxicities in rodents and primates. However, at doses currently under evaluation in the clinic, phosphorothioate oligo-deoxynucleotides have been well tolerated. In addition, there is evidence that phosphorothioate oligodeoxynucleotides provide clinical benefits to patients with viral infections, cancer, and inflammatory diseases. There are several phosphorothio-ate oligodeoxynucleotides in late-stage clinical trials, which will hopefully deliver more effective therapies for patients suffering from life-threatening or very debilitating diseases.

Extensive medicinal chemistry efforts have been successfully focused on identifying improved antisense oligonucleo-tides, which address some of these issues. There are at least 4 areas in which chemistry can add value to first-generation drugs: increase potency, decrease toxicity, alter pharmacoki-netics, and lower costs. As an example, numerous modified oligonucleotides have been identified that have a higher affinity for target RNA than phosphorothioate oligodeoxynucleo-tides (84,87,91-93,316). Oligonucleotide modifications have been identified that exhibit increased resistance to serum and cellular nucleases, enabling use of oligonucleotides that do not have phosphorothioate linkages. The tissue distribution of oligonucleotides may be altered with either chemical modifications or formulations (79,134,140,141,143,144,181, 200,203). Preliminary data also suggest that oral delivery of antisense oligonucleotides may be feasible (141). Finally, a number of modified oligonucleotides have been described that potentially exhibited less toxicities than first-generation phos-phorothioate oligodeoxynucleotides (78,149,178)]. However, as experience with these modified oligonucleotides is rather limited, it remains to be seen whether they will have a distinct toxicity profile.

In conclusion, first-generation phosphorothioate oligode-oxynucleotides have proven to be valuable pharmacological tools for the researcher and have produced new therapies for the patient. Identification of improved second-and third-generation oligonucleotides with novel formulation should better therapies for patients. Although tremendous progress has been made for antisense technology during the past 14 years, there are many more questions that remain for the technology.

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