Tiny LNA-Based Compounds Inhibit Entire Disease-Associated MicroRNA Families

The bridge "locks” the ribose in the 3'-endo conformation. LNA nucleotides can be mixed with DNA or RNA residues in the oligonucleotide whenever desired. The locked ribose conformation enhances base stacking and backbone preorganization. This significantly increases the hybridization properties (melting temperature) of oligonucleotides.

Investigators at Santaris Pharma A/S (Hoersholm, Denmark) have been developing clinical applications for LNA-based drug compounds. For this purpose, they have employed their proprietary LNA Drug Platform technology.

Results have been published in the March 20, 2011, online edition of the journal Nature Genetics. The data accumulated during this study show that the high affinity and target specificity of tiny LNA-based compounds enabled functional inhibition of entire miRNA families in a range of tissues without off-target effects.

Transfection of tiny LNAs into cells resulted in simultaneous inhibition of miRNAs within families sharing the same seed with concomitant upregulation of direct target genes. In addition, systemically delivered, unconjugated tiny LNAs showed uptake in many normal tissues and in breast tumors in mice, coinciding with long-term miRNA silencing. The tiny LNA-based compounds were well tolerated by mice and could be delivered without the use of complex delivery vehicles.

"Using tiny LNA-based compounds to successfully inhibit entire disease-associated miRNA families provides a new range of opportunities to develop novel miRNA-targeted drugs for both in-house drug discovery programs, as well as with our partners,” said Dr. Henrik Ørum, CSO of Santaris Pharma A/S. "The versatility of our proprietary LNA Drug Platform has the potential to develop new modalities to target a broad range of diseases, including cardiometabolic disorders, infectious and inflammatory diseases, and cancer by targeting miRNAs, entire miRNA families or mRNAs.”

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