An increasing number of studies support the involvement of long non-coding RNAs (lncRNAs) in cancer. Targeting lncRNAs is an appealing opportunity as lncRNA expression can be highly tissue-specific, potentially reducing toxic side-effects in normal cells. Nevertheless, therapeutic targeting of lncRNAs remains quite a challenging endeavor. As ASO technology is advancing in the clinic, several limitations have surfaced. Most notably, chemically modified phosphorothioate (PS) gapmer ASOs bind many intracellular proteins with high avidity, thereby mislocalizing them and altering their function and stability in an RNase H1-dependent manner, effectively inducing apoptosis and thus treatment toxicity. Steric blocking ASOs do not recruit RNase H1 as they do not contain a DNA gap, but rather are built entirely from RNA nucleotides. 2’ modifications of these nucleotides, such as 2’MOE, have been shown to completely mitigate the cytotoxic effects that are induced by the PS backbone. Currently 7 out of 10 clinically approved ASOs are fully modified ASOs (i.e. containing both PS and 2’ modifications on all nucleotides) that block interactions between the splicing machinery and splice junctions in specific mRNAs to alter splicing. However, fully modified ASOs can also be exploited to block the binding between RNA and other proteins. To efficiently develop such ASOs, one must be able to map RNA-protein interfaces. We aim to identify RNA-protein interaction interfaces of cancer-specific lncRNAs with the intent to develop ASOs that sterically block these interactions and evaluate the therapeutic potential of these ASOs in vivo.
PhD in Health Sciences, 2022
Master of Sciences, Cell and Systems Biology, 2015
University of Antwerp