Gymnosis is the process of the delivery of antisense
oligodeoxynucleotides to cells, in the absence of any carriers or conjugation, that produces sequence-specific gene silencing. While gymnosis was originally demonstrated using
locked nucleic acid (LNA) gapmers, 2'-deoxy-2'fluroarabinonucleic
acid (2'F-ANA) phosphorothioate gapmer
oligonucleotides (oligos) when targeted to the Bcl-2 and
androgen receptor (AR) mRNAs in multiple cell lines in tissue culture, are approximately as effective at silencing of Bcl-2 expression as the iso-sequential LNA congeners. In LNCaP
prostate cancer cells, gymnotic silencing of the AR by a
2'F-ANA phosphorothioate gapmer oligo led to downstream silencing of cellular
prostate-specific antigen (PSA) expression even in the presence of the androgenic
steroid R1881 (
metribolone), which stabilizes cytoplasmic levels of the AR. Furthermore, gymnotic silencing occurs in the absence of serum, and silencing by both LNA and
2'F-ANA oligos is augmented in serum-free (SF) media in some cell lines when they are treated with
oleic acid and a variety of ω-6
polyunsaturated fatty acids (ω-6 PUFAs), but not by an aliphatic (palmitic)
fatty acid. These results significantly expand our understanding of and ability to successfully manipulate the cellular delivery of
single-stranded DNA molecules in vitro.Molecular
Therapy -
Nucleic Acids (2012) 1, e43; doi:10.1038/mtna.2012.35; advance online publication 18 September 2012.