Therapeutics


Figure 1 Delivery and mechanism of


action for different classes of RNA-based therapeutics. RNA-based therapeutics including mRNA, siRNA, miRNA and antisense RNA, represented here as magenta


rods, can be delivered via non- specific uptake using lipid nanoparticle (LNP) and polymer systems, or via receptor-mediated uptake


using aptamer-, N-Acetyl-D- galactosamine (GalNAc)- or antibody-conjugate systems. Following endosome escape,


single-stranded IVT mRNA can replace proteins in vivo that


are not expressed/expressed at low level or are non- functional, whereas single-


stranded antisense RNA or double-stranded RNAi therapeutics (miRNA and


siRNA) attenuate or abolish protein production.


Furthermore, RNA aptamers can block protein-protein or receptor-ligand interactions,


disrupting the function of the target protein


bind to RNA without activating RNase H. Modified antisense RNAs exhibit significantly-improved tis- sue half-life and prolonged inhibitory activity. To date, two antisense RNA drugs have gained FDA approval: Spinraza (Biogen Inc) and Exondys 51 (Sarepta Therapeutics Inc) (Table 1).


RNAi: miRNA and siRNA The cellular process of RNAi utilises miRNAs and


20


siRNAs to silence gene expression through post- translational gene silencing or transcriptional silencing. Double-stranded miRNAs and siRNAs bind to mRNA and inhibit protein translation. Endogenous miRNAs induce translational repres- sion and mRNA degradation when the antisense strand displays limited complementarity to the tar- get mRNA, whereas sequence-specific cleavage is exploited by exogenous siRNAs that display perfect


Drug Discovery World Fall 2018


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