RNA Interference Pathways and Therapeutic Exploitation - RNA Interference from Biology to Therapeutics - page 17

While awaiting the clinical success of siRNA therapeutics, our knowledge of
natural gene silencing pathways, RNAi-mediated or not, is expanding. In particular,
the mapping of regulation and deregulation of miRNA expression in human dis-
eases holds both diagnostic/prognostic and therapeutic value. Strategies for replen-
ishing miRNAs downregulated or lost in human disease by introducing miRNA
mimics or conversely inhibiting aberrantly expressed miRNAs via synthetic anti-
miRs are most likely to gain even greater popularity in the near future. Also, the
combination of siRNAs targeting particular detrimental mRNA and miRNA mimics/
anti-miRs restoring natural miRNA pathway functions is likely to prove a powerful
therapeutic cocktail.
Although the reported transcriptional silencing by promoter-targeting siRNAs
[ 233 ] seem to require more investigations to be relevant for RNA therapeutics [ 234 ] ,
the investigations of epigenetic remodeling by natural short and long noncoding
RNA (ncRNA) may very well establish novel siRNA targets or even bedrock novel
silencing molecules [ 235, 236 ] .
Finally, non-RNAi-mediated gene silencing is currently also flourishing; impor-
tant progress in vivo is already being made with RNAi-independent chemically
engineered antisense oligonucleotides (ASO) which are short ~20-nt single-stranded
antisense oligonucleotides designed to trigger degradation of a given target mRNA
upon binding [ 237, 238 ]. Alternatively, several types of so-called steric-blocking
oligonucleotides, most typically 20-25-nt single-stranded chemically modified oli-
gonucleotides or phosphorodiamidate morpholino oligos (PMOs), have proven
capable of blocking RNA-binding protein, reducing mRNA translation and modu-
late mRNA splicing and folding, with some success in clinical trials [ 66, 239- 243 ] .
The arsenal of promising nucleic acid-based therapeutics seems quite powerful
~10 years after the first successful application of siRNA in human cells [ 244 ] . We
believe nucleic acid-based therapeutics have now properly matured and are on the
verge of clinical breakthroughs, a natural progression not dissimilar to development
of monoclonal antibody therapeutics pioneered in the 1970-1980s.
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