Journal Article

I02 Therapeutic effect of antisense oligonucleotide treatment in YAC128 Huntington mice

Weerd, Louise van der, Overzier, Maurice, Suidgeest, Ernst, Roon-Mom, Willeke van, Kuijper, Elsa, Toonen, Lodewijk

2022

Overview

BackgroundIn Huntington’s Disease (HD), cellular toxicity is particularly caused by fragments of the mutant huntingtin (HTT) protein generated by proteolytic enzymes. Lowering the levels of these toxic HTT protein fragments is hypothesized to ameliorate the consequences mutant HTT. To that end, we have developed an antisense oligonucleotide (AON) that targets HTT pre-mRNA and induces skipping of exon 12. As exon 12 contains the critical proteolytic cleavage site, the resulting HTTΔ12 protein can no longer be cleaved into its toxic fragments.AimWe aimed to determine whether skipping of exon 12 in HTT mRNA could rescue the phenotype of YAC128 mice, a model of HD that contains the full-length human HTT gene including 128 CAG-repeats.MethodsIn total 1500 µg AON was administered via three intracerebroventricular injections starting at 6 months of age. We monthly assessed motor behaviour using a rotarod and studied (hypo)activity using PhenoTyper cages (Noldus). At 12 months of age, MRI was performed to assess cerebral volume, followed by sacrifice and brain isolation for analysis of exon skip efficiency and neuropathology.ResultsAON treatment induced around 40% exon 12 skip on RNA level in the cortex of YAC128 mice. We observed a rescue of the YAC128 phenotype on body weight and activity levels by AON-mediated exon 12 skipping. However, the phenotype observed on the rotarod was not restored.ConclusionsSo far, in vivo treatment results are promising. We are currently working on confirming HTT protein modification and assessing neuropathology using immunohistochemistry, MRI data and gene expression analysis.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group LTD
• Subject: antisense oligonucleotide / exon skipping / Gene expression / Genotype & phenotype / Huntingtons disease / I: Experimental therapeutics – preclinical / Neuropathology / Proteins / YAC128