7572
Biochemistry 2007, 46, 7572-7580
Inhibiting Gene Expression with Locked Nucleic Acids (LNAs) That Target Chromosomal DNA† Randall L. Beane,‡ Rosalyn Ram,‡ Sylvie Gabillet,§ Khalil Arar,§ Brett P. Monia,| and David R. Corey*,‡ Departments of Pharmacology and Biochemistry, UniVersity of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Road, Dallas, Texas 75390-9041, SIGMA-Proligo Genopole Campus 1, 5 rue Desbrue` res, 91030 EVry Cedex, France, and ISIS Pharmaceutical, Carlsbad, California 92008 ReceiVed February 2, 2007; ReVised Manuscript ReceiVed April 16, 2007
ABSTRACT:
Oligonucleotides containing locked nucleic acid bases (LNAs) have increased affinity for complementary DNA sequences. We hypothesized that enhanced affinity might allow LNAs to recognize chromosomal DNA inside human cells and inhibit gene expression. To test this hypothesis, we synthesized antigene LNAs (agLNAs) complementary to sequences within the promoters of progesterone receptor (PR) and androgen receptor (AR). We observed inhibition of AR and PR expression by agLNAs but not by analogous oligomers containing 2′-methoxyethyl bases or noncomplementary LNAs. Inhibition was dose dependent and exhibited IC50 values of
