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Experimental therapeutics—preclinical
P01 Antisense oligonucleotide mediated transcript reduction and modulation—the European approach to develop a therapy for Huntington disease
  1. WMC van Roon-Mom1,
  2. MM Evers1,
  3. HD Tran1,
  4. JCT van Deutekom2,
  5. SAM Mulders2,
  6. AM Aartsma-Rus1,
  7. JT den Dunnen1,3,
  8. G-JB van Ommen1
  1. 1Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  2. 2Prosensa Therapeutics B.V., Leiden, The Netherlands
  3. 3Genome Technology Center, Leiden University Medical Center, Leiden, The Netherlands


There has been a recent surge in research using antisense oligonucleotides (AONs) to reduce huntingtin transcript levels and thus huntingtin protein levels both in vitro an in vivo. This can be done in a non-allele specific manner by targeting both mutant and normal huntingtin transcripts but preferred would be an allele specific approach targeting mutant huntingtin transcripts through SNP-specific AONs or by use of triplet-repeat AONs complementary towards the (CAG)n expansion. Studies in our group and others have confirmed the feasibility of this approach. The disadvantage however is that there is a reduction in huntingtin protein levels and lowering huntingtin levels too much will cause unwanted side effects. Fortunately, AONs are a versatile tool that can also be exploited to induce inclusion or exclusion of target exons, thereby modulating the translated protein product. It is known that caspase 6 cleavage at aa 586 gives rise to a toxic N-terminal huntingtin fragment, and mutation of this site in the YAC128 mouse model (C6R-YAC128 by the group of Michael Hayden) provides protection from neuronal dysfunction and neurodegeneration. This (and other) caspase cleavage sites are encoded by exon 12 of the HTT gene. By skipping this exon with AONs, a shorter huntingtin protein will be formed lacking the caspase cleavage sites, without altering overall huntingtin protein levels. We propose a combinatorial AON approach for Huntington disease, making use of the transcript reducing properties of (CUG)7 AONs that preferentially targets mutant huntingtin transcripts, as well as the transcript modifying AONs that remove important caspase cleavage sites from the huntingtin protein.

  • Antisense oligonucleotide
  • transcript reduction
  • exon skipping

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