Abstract Details

Title WVE-004, an investigational stereopure antisense oligonucleotide for the treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S20 - Motor Neuron Disease/Amyotrophic Lateral Sclerosis (2:40 PM-2:48 PM)

Poster/Presentation
Number 005

Objective

To determine the effects of WVE-004 on C9orf72 G₄C₂ repeat-containing transcripts, DPR proteins, and C9orf72 protein levels.

Background

A large G₄C₂ repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeat expansion reduces gene expression and produces pathogenic RNA foci and dipeptide repeat (DPR) proteins. Wave Life Sciences is developing an investigational oligonucleotide, WVE-004, as a potential therapy for ALS and FTD.

Design/Methods WVE-004 in vitro activity was assessed in patient-derived induced pluripotent stem cell (iPSC) motor neurons under gymnotic conditions. In vivo activity and distribution were assessed in BAC transgenic mice containing the full human C9orf72 gene with repeat expansion. Mice were given intracerebroventricular (ICV) injections of WVE-004 (50 µg) or PBS at day 0 and day 7. Transcript levels were analyzed using qPCR (Taqman assay), poly-GP DPR was measured by Meso Scale Discovery (MSD) assay. Relative C9orf72 protein levels were measured by Wes capillary-based immunoassay, normalized to HPRT. Oligonucleotides in situ were visualized using ViewRNA® (ThermoFisher Scientific).

Results WVE-004 potently and selectively reduced repeat-containing transcripts in iPSC motor neurons (IC₅₀ 201.7 nM). In transgenic mice, WVE-004 reduced repeat-containing transcripts by 60-80% (p<0.0001) in spinal cord and by 40-50% (p<0.0001) in cortex 6 months after dosing. WVE-004 reduced DPRs by 94.2% (p=0.001) and 87% (p<0.0001) in spinal cord and cortex, respectively, at 6 months. Total C9orf72 protein levels were unaffected. Histochemistry demonstrated widespread and sustained WVE-004 distribution in the nuclei of neurons in the brain including spinal cord and cortex.

Conclusions In transgenic mice, WVE-004 produces substantial reductions in repeat-containing C9orf72 transcripts and DPR proteins without disrupting total protein expression, sustained for at least 6 months. These results support further development of WVE-004 in patients with C9orf72-associated ALS and FTD.

Authors/Disclosures
Yuanjing Liu PRESENTER	Yuanjing Liu has received personal compensation for serving as an employee of Wave life sciences . Yuanjing Liu has received stock or an ownership interest from Wave life sciences.
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Chandra Vargeese	No disclosure on file

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