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. 2022 Nov;37(11):2184-2190.
doi: 10.1002/mds.29201. Epub 2022 Aug 29.

Targeted Molecular Therapeutics for Parkinson's Disease: A Role for Antisense Oligonucleotides?

Dunhui Li  1   2   3 , Frank L Mastaglia  1   2 , Wai Yan Yau  1 , Shengdi Chen  4 , Steve D Wilton  1   2 , Patrick A Akkari  1   2   5
Affiliations

Targeted Molecular Therapeutics for Parkinson's Disease: A Role for Antisense Oligonucleotides?

Dunhui Li et al. Mov Disord. 2022 Nov.
No abstract available

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Conflict of interest statement

D.L. receives salary support from the philanthropic Giumelli Family Foundation. S.D.W. is a consultant to Sarepta Therapeutics and is named as an inventor on Duchenne muscular dystrophy exon‐skipping patents licensed through the University of Western Australia to Sarepta Therapeutics (Cambridge, MA, USA) and as such is entitled to milestone and royalty payments. P.A.A. is the Chief Scientific Officer of and receives salary support from Black Swan Pharmaceuticals (Wake Forest, NC, USA). Full financial disclosures and author roles may be found in the online version of this article.

Figures

FIG 1
FIG 1
Major mechanisms of action of antisense oligonucleotides. General information flow of protein‐coding genes (Ai–iii): DNA transcribed to pre‐mature RNA (pre‐mRNA) (i); pre‐mRNA processed to mature RNA (mRNA) (ii), which is translated to protein (iii); RNaseH‐inducing ASOs, normally gapmers, can degrade targeted transcripts in the cytoplasm (B) and nucleus (C). Splice‐modulating ASOs can skip an out‐of‐frame exon to create a premature stop codon, which induces non‐sense‐mediated decay (NMD) of a gene of interest (D). Splice‐switching ASOs can also generate an alternative transcript that could translate to a shorter and alternatively spliced protein isoform (E). The polyadenylation site of a targeted transcript can be altered by placing an ASO against either a proximal or distal polyadenylation signal, which could result in an unstable or a more stable transcript and the resulting reduced or increased protein production (F). ASOs can sterically block the translation initiation complex, block the ribosome, and inhibit mRNA translation (G). Through targeting microRNA binding sites (miRBs) (H) or specifically binding to microRNAs (miR) (I), ASOs can inhibit the functions of microRNAs to stabilize mRNA transcript to increase expression. By sterically blocking the upstream AUG (uA) in the upstream open reading frame or inhibitory motifs residing in the 5′ untranslated region, ASOs could enhance targeted transcript translation and increase the expression of the corresponding protein (J). [Color figure can be viewed at wileyonlinelibrary.com]
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