NONCODOWN · Optimizing Antisense Oligonucleotides for Efficient and Specific Knockdown of Nuclear Non-Coding RNA

The past decade has seen a dramatic increase in discovery of noncoding RNA with functional regulatory roles in the nucleus of mammalian cells. Yet tools to manipulate these nuclear noncoding RNAs remain inadequate. This proposal will develop optimized antisense oligonucleotides for targeting and degrading structured RNAs in the nucleus. This will be carried out by using both the best of what already exists in the field of nucleic acid chemistry (e.g. locked nucleic acid and the gapmer approach) and innovative new designs (e.g. CuAAC-derived PNA-DNA-LNA chimeric oligomers for degrading structured RNA targets).