We've bee using morpholino or fully posphorothioated backbone, but I read the initial ASO paper from the 1970s and just straight up DNA was used. I am wondering if I could use these at least to do our initial tests looking for which length and sequence seems to work best, it would be much cheaper.
The modifications in morpholinos and phosphorothioate oligos can alter their ASO activity. While unmodified DNA can be used as an ASO, the differences in binding affinity and nuclease resistance will make it hard to compare to the modified ASOs.
You may try, but it is not recommended. Oligonucleotide phosphorothioates are made as readily as the respective natural phosphates and are insignificantly more expensive. It is not worth the risk of obtaining false-negative results by using oligos with natural backbone.
Oligonucleotides with natural backbone are readily degraded by nucleases present in biological material. Half-life of a DNA oligo in serum is less than 1 min. In their ground-breaking work Paul Zamecnik and his group were using natural oligonucleotides indeed, but these were capped at the 3'-terminus with various groups, for instance with phenylcarbamate to afford a somewhat higher stability.
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