Preclinical evaluation of WVE-004, an investigational stereopure oligonucleotide for the treatment of C9orf72-associated ALS or FTD

Liu, Yuanjing; Andreucci, Amy; Iwamoto, Naoki; Yin, Yuan; Yang, Hailin; Liu, Fangjun; Bulychev, Alexey; Hu, Xiheng; Lin, Xuena; Lamore, Sarah D.; Patil, Sunil; Mohapatra, Susovan; Purcell-Estabrook, Erin; Taborn, Kristin; Dale, Elena; Vargeese, Chandra

doi:10.1016/j.omtn.2022.04.007

Cited by 30 publications

(17 citation statements)

References 58 publications

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“…We have previously shown the importance of controlling backbone chemistry and chirality for other oligonucleotide modalities such as RNase H-mediated silencing ( 11 , 28 , 44 ), splice modulation ( 24 ), and RNA base editing with ADAR ( 25 ), and we now extend the application of these finding from our initial work on siRNA-mediated silencing ( https://patents.google.com/patent/WO2014012081A2/en?oq=WO2014012081 ) and the subsequent work of others ( 31 , 32 ) to confirm control over PS chirality improves siRNA-mediated silencing. Previously published reports limited evaluation of chirality to a single PS linkage at the terminals or a small number of stereoisomers ( 31 , 32 ).…”

Section: Discussionmentioning

confidence: 99%

Impact of stereopure chimeric backbone chemistries on the potency and durability of gene silencing by RNA interference

Liu

Iwamoto

Marappan

et al. 2023

Nucleic Acids Research

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Herein, we report the systematic investigation of stereopure phosphorothioate (PS) and phosphoryl guanidine (PN) linkages on siRNA-mediated silencing. The incorporation of appropriately positioned and configured stereopure PS and PN linkages to N-acetylgalactosamine (GalNAc)-conjugated siRNAs based on multiple targets (Ttr and HSD17B13) increased potency and durability of mRNA silencing in mouse hepatocytes in vivo compared with reference molecules based on clinically proven formats. The observation that the same modification pattern had beneficial effects on unrelated transcripts suggests that it may be generalizable. The effect of stereopure PN modification on silencing is modulated by 2′-ribose modifications in the vicinity, particularly on the nucleoside 3′ to the linkage. These benefits corresponded with both an increase in thermal instability at the 5′-end of the antisense strand and improved Argonaute 2 (Ago2) loading. Application of one of our most effective designs to generate a GalNAc-siRNA targeting human HSD17B13 led to ∼80% silencing that persisted for at least 14 weeks after administration of a single 3 mg/kg subcutaneous dose in transgenic mice. The judicious use of stereopure PN linkages improved the silencing profile of GalNAc-siRNAs without disrupting endogenous RNA interference pathways and without elevating serum biomarkers for liver dysfunction, suggesting they may be suitable for therapeutic application.

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Section: Discussionmentioning

confidence: 99%

Impact of stereopure chimeric backbone chemistries on the potency and durability of gene silencing by RNA interference

Liu

Iwamoto

Marappan

et al. 2023

Nucleic Acids Research

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“…Biogen’s IONIS-C9Rx is an ASO targeting the C9orf72 open reading frame mRNA, which is aimed at reducing the DPRs translated from the expansion. Similarly, Wave Life Science’s WVE-3972–01 is a sterically pure ASO targeting downregulation of DPRs and pathogenic C9orf72- derived RNA transcripts and claims to have kept intact the healthy C9orf72 transcriptional V2 variants ( Liu et al, 2022 ). These treatments aim to address downstream effects within the cell.…”

Section: Discussionmentioning

confidence: 99%

Reduced C9orf72 expression exacerbates polyGR toxicity in patient iPSC-derived motor neurons and a Type I protein arginine methyltransferase inhibitor reduces that toxicity

Dane

Gill

Vieira

et al. 2023

Front. Cell. Neurosci.

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IntroductionIntronic repeat expansions in the C9orf72 gene are the most frequent known single genetic causes of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These repeat expansions are believed to result in both loss-of-function and toxic gain-of-function. Gain-of-function results in the production of toxic arginine-rich dipeptide repeat proteins (DPRs), namely polyGR and polyPR. Small-molecule inhibition of Type I protein arginine methyltransferases (PRMTs) has been shown to protect against toxicity resulting from polyGR and polyPR challenge in NSC-34 cells and primary mouse-derived spinal neurons, but the effect in human motor neurons (MNs) has not yet been explored.MethodsTo study this, we generated a panel of C9orf72 homozygous and hemizygous knockout iPSCs to examine the contribution of C9orf72 loss-of-function toward disease pathogenesis. We differentiated these iPSCs into spinal motor neurons (sMNs).ResultsWe found that reduced levels of C9orf72 exacerbate polyGR15 toxicity in a dose-dependent manner. Type I PRMT inhibition was able to partially rescue polyGR15 toxicity in both wild-type and C9orf72-expanded sMNs.DiscussionThis study explores the interplay of loss-of-function and gain-of-function toxicity in C9orf72 ALS. It also implicates type I PRMT inhibitors as a possible modulator of polyGR toxicity.

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“…Details of the clinical trial have not yet been published. Although the initial ASO trial failed, Phase 1b/2a clinical trial of another ASO targeting C9‐FTD/ALS (WVE‐004) (Liu et al, 2022) is now underway (NCT04931862). Moreover, the other ASO designated afinersen, which selectively targets C9orf72 V1 and V3 transcript, while sparing V2 transcript, demonstrated reduced poly‐GP level in CSF of an C9‐ALS patient, validating its target engagement effect (Tran et al, 2022).…”

Section: Future Therapeutic Interventionmentioning

confidence: 99%

Aspects of degradation and translation of the expanded C9orf72 hexanucleotide repeat RNA

Mori

Gotoh

Ikeda

2023

Journal of Neurochemistry

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An hexanucleotide repeat expansion mutation in the non-coding region of C9orf72 gene causes frontotemporal dementia and amyotrophic lateral sclerosis. This mutation is estimated to be the most frequent genetic cause of these currently incurable diseases. Since the mutation causes autosomal dominantly inherited diseases, disease cascade essentially starts from the expanded DNA repeats. However, molecular disease mechanism is inevitably complex because possible toxic entity for the disease is not just functional loss of translated C9ORF72 protein, if any, but potentially includes bidirectionally transcribed expanded repeat containing RNA and their unconventional repeat-associated non-AUG translation products in all possible reading frames. Although the field learned so much about the disease since the identification of the mutation in 2011, how the expanded repeat causes a particular type of frontotemporal lobe dominant neurodegeneration and/or motor neuron degeneration is not yet clear. In this review, we summarize and discuss the current understandings of molecular mechanism of this repeat expansion mutation with focuses on the degradation and translation of the repeat containing RNA transcripts.

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Preclinical evaluation of WVE-004, an investigational stereopure oligonucleotide for the treatment of C9orf72-associated ALS or FTD

Cited by 30 publications

References 58 publications

Impact of stereopure chimeric backbone chemistries on the potency and durability of gene silencing by RNA interference

Impact of stereopure chimeric backbone chemistries on the potency and durability of gene silencing by RNA interference

Reduced C9orf72 expression exacerbates polyGR toxicity in patient iPSC-derived motor neurons and a Type I protein arginine methyltransferase inhibitor reduces that toxicity

Aspects of degradation and translation of the expanded C9orf72 hexanucleotide repeat RNA

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