Antisense technology: A review

Crooke, Stanley T.; Liang, Xiaojing; Baker, Brenda F.; Crooke, Rosanne M.

doi:10.1016/j.jbc.2021.100416

Cited by 205 publications

(214 citation statements)

References 200 publications

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“…When comparing the efficacy of these AONs based on the chemical modifications, we could indeed see that the 2′- O -MOE-PS AONs were more potent than the 2′-OMe-PS AONs ( Supplementary Figure S5 ). This is in line with previous reports showing that the 2′- O -MOE-PS AONs have increased potency [ 39 , 51 ]. Previously, we reported that for this PE insertion, one mismatch was enough to abolish the splicing-switching capacity of the AON [ 32 ].…”

Section: Discussionsupporting

confidence: 93%

Antisense Oligonucleotide-Based Rescue of Aberrant Splicing Defects Caused by 15 Pathogenic Variants in ABCA4

Tomkiewicz

Suárez-Herrera

Cremers

et al. 2021

IJMS

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The discovery of novel intronic variants in the ABCA4 locus has contributed significantly to solving the missing heritability in Stargardt disease (STGD1). The increasing number of variants affecting pre-mRNA splicing makes ABCA4 a suitable candidate for antisense oligonucleotide (AON)-based splicing modulation therapies. In this study, AON-based splicing modulation was assessed for 15 recently described intronic variants (three near-exon and 12 deep-intronic variants). In total, 26 AONs were designed and tested in vitro using a midigene-based splice system. Overall, partial or complete splicing correction was observed for two variants causing exon elongation and all variants causing pseudoexon inclusion. Together, our results confirm the high potential of AONs for the development of future RNA therapies to correct splicing defects causing STGD1.

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Section: Discussionsupporting

confidence: 93%

Antisense Oligonucleotide-Based Rescue of Aberrant Splicing Defects Caused by 15 Pathogenic Variants in ABCA4

Tomkiewicz

Suárez-Herrera

Cremers

et al. 2021

IJMS

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“…Gapmers are AONs designed to recruit RNase H to degrade mRNA in a targeted fashion [ 72 ]. RNase H is a globally expressed endogenous endoribonuclease [ 73 ] capable of cleavage of a phosphodiester bond of an RNA molecule in the context of an RNA-DNA duplex [ 74 ].…”

Section: Antisense Mechanisms: Gapmers Sirnas and Splice-modulating Oligonucleotidesmentioning

confidence: 99%

From Antisense RNA to RNA Modification: Therapeutic Potential of RNA-Based Technologies

Adachi

Hengesbach

et al. 2021

Biomedicines

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Therapeutic oligonucleotides interact with a target RNA via Watson-Crick complementarity, affecting RNA-processing reactions such as mRNA degradation, pre-mRNA splicing, or mRNA translation. Since they were proposed decades ago, several have been approved for clinical use to correct genetic mutations. Three types of mechanisms of action (MoA) have emerged: RNase H-dependent degradation of mRNA directed by short chimeric antisense oligonucleotides (gapmers), correction of splicing defects via splice-modulation oligonucleotides, and interference of gene expression via short interfering RNAs (siRNAs). These antisense-based mechanisms can tackle several genetic disorders in a gene-specific manner, primarily by gene downregulation (gapmers and siRNAs) or splicing defects correction (exon-skipping oligos). Still, the challenge remains for the repair at the single-nucleotide level. The emerging field of epitranscriptomics and RNA modifications shows the enormous possibilities for recoding the transcriptome and repairing genetic mutations with high specificity while harnessing endogenously expressed RNA processing machinery. Some of these techniques have been proposed as alternatives to CRISPR-based technologies, where the exogenous gene-editing machinery needs to be delivered and expressed in the human cells to generate permanent (DNA) changes with unknown consequences. Here, we review the current FDA-approved antisense MoA (emphasizing some enabling technologies that contributed to their success) and three novel modalities based on post-transcriptional RNA modifications with therapeutic potential, including ADAR (Adenosine deaminases acting on RNA)-mediated RNA editing, targeted pseudouridylation, and 2′-O-methylation.

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“…The dimethyl amino moiety of the phosphoramidate in PMO can also be replaced by a piperazine, which is positively charged under physiological condition. And this positively charged PMO is termed PMOplus (for reviews in ASO drug development, see [173][174][175][176]).…”

Section: The Chemical Space Of Rna Splicing Modifiers 41 Chemical Modification Of Asomentioning

confidence: 99%

RNA-Targeting Splicing Modifiers: Drug Development and Screening Assays

et al. 2021

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RNA splicing is an essential step in producing mature messenger RNA (mRNA) and other RNA species. Harnessing RNA splicing modifiers as a new pharmacological modality is promising for the treatment of diseases caused by aberrant splicing. This drug modality can be used for infectious diseases by disrupting the splicing of essential pathogenic genes. Several antisense oligonucleotide splicing modifiers were approved by the U.S. Food and Drug Administration (FDA) for the treatment of spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). Recently, a small-molecule splicing modifier, risdiplam, was also approved for the treatment of SMA, highlighting small molecules as important warheads in the arsenal for regulating RNA splicing. The cellular targets of these approved drugs are all mRNA precursors (pre-mRNAs) in human cells. The development of novel RNA-targeting splicing modifiers can not only expand the scope of drug targets to include many previously considered “undruggable” genes but also enrich the chemical-genetic toolbox for basic biomedical research. In this review, we summarized known splicing modifiers, screening methods for novel splicing modifiers, and the chemical space occupied by the small-molecule splicing modifiers.

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Antisense technology: A review

Cited by 205 publications

References 200 publications

Antisense Oligonucleotide-Based Rescue of Aberrant Splicing Defects Caused by 15 Pathogenic Variants in ABCA4

Antisense Oligonucleotide-Based Rescue of Aberrant Splicing Defects Caused by 15 Pathogenic Variants in ABCA4

From Antisense RNA to RNA Modification: Therapeutic Potential of RNA-Based Technologies

RNA-Targeting Splicing Modifiers: Drug Development and Screening Assays

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