Article Text

Experimental therapeutics—preclinical
P02 In vivo efficacy of (CUG)n oligonucleotides to treat HD
  1. SAM Mulders1,
  2. R Vlamings2,
  3. A Jahanshahianvar2,
  4. J van de Giessen1,
  5. JCT van Deutekom1,
  6. Y Temel2
  1. 1Prosensa Therapeutics B.V., Leiden, The Netherlands
  2. 2Departments of Neuroscience and Neurosurgery, Maastricht University Medical Center, Maastricht, The Netherlands


Background Huntington's disease (HD) is caused by an expanded (CAG)n tract in the Huntingtin gene (HTT) that is translated into an expanded polyglutamine (polyQ) stretch in the protein. The polyQ stretch causes a toxic gain of function and plays a central role in the disease. Currently no therapy is available to overcome HD.

Aim We hypothesise that direct silencing of prolonged (CAG)n transcripts offers the most straightforward solution for improvement of HD features in patients. Previously we have shown that PS57, a (CUG)7 2’-O-methyl phosphorothioate antisense oligonucleotide (AON), can efficiently reduce huntingtin transcripts and protein levels when transfected in patient derived HD fibroblasts1

Methods and Results We report here on the effect of PS57, with more advanced oligochemistry, in symptomatic transgenic HD rats2 in vivo. The rats, carrying a truncated huntingtin cDNA fragment with 51 CAG repeats under the control of the native rat huntingtin promoter, received 15 times an injection in the right lateral ventricle with the chemically modified PS57 during 18 weeks. Behavioural assessments including motor and cognitive performance in combination with mood and anxiety tests were performed on a monthly base. Various brain tissues were isolated and Q-RT-PCR analysis revealed silencing of expanded Htt transcript levels after treatment compared to control rats. Effects on Htt protein level and histological evaluation of brain sections both from treated as control rats are currently being analysed.

Conclusion In summary, we conclude that use of (CUG)n triplet repeat AONs in HD has therapeutic potential, and that results so far offer interesting openings for future studies.

References 1. Evers MM, et al. Plos One 2011.

2. Hörsten von S, et al. Hum Mol Genet 2003.

  • Triplet repeat antisense oligonucleotides
  • allele specific silencing

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