To the editor:

I would like to clarify a point in the encouraging Feature article entitled “Antisense and Sensibility?” published in the February issue (Nat. Biotechnol. 20, 121, 2002). Phosphorothioates are correctly cited as the first generation of antisense oligonucleotides. Although it is true that these oligonucleotides are usually associated with undesirable side effects, second-generation oligonucleotides, such as methoxyethyl constructs, also rely on this modification for in vivo application. Moreover, the immune-stimulating CpG oligonucleotides currently used for clinical trials also contain them. For some reason, the side effects are not apparent in the second-generation context, and not with the CpG oligomers because of the very low concentrations needed.