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Experimental therapeutics: preclinical
B09 One antisense oligonucleotide as a potential therapy for polyglutamine disorders
  1. W M C van Roon-Mom1,
  2. M M Evers1,
  3. J C T van Deutekom2,
  4. S A M Mulders2,
  5. A M Aartsma-Rus1,
  6. J T den Dunnen1,3,
  7. G-J B van Ommen1
  1. 1Centre for Human and Clinical Genetics, Leiden University Medical Centre, Albinusdreef 2, Leiden, The Netherlands
  2. 2Prosensa Therapeutics BV, Wassenaarseweg 72, Leiden, The Netherlands
  3. 3Genome Technology Centre, Leiden University Medical Centre, Albinusdreef 2, Leiden, The Netherlands


Background To date there are nine known polyglutamine (polyQ) disorders: spinal bulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), Huntington's disease (HD) and spinocerebellar ataxias (SCA1, 2, 3, 6, 7, and 17). These diseases are all caused by an expansion of CAG repeats in a gene that is translated into an expanded polyglutamine stretch. A hallmark of these diseases is the accumulation of protein aggregates in the brain. The polyglutamine expansion results in a toxic gain of function for the protein and plays a central role in the disease. The size of this expansion has a direct link to the aggregation proneness as well as the severity of pathological and clinical features.

Aim To reduce expanded CAG repeat transcript and protein levels in patient derived polyQ cell lines.

Methods Previously we have shown that fully modified 2'OMePS antisense oligonucleotides (AONs) can effectively reduce huntingtin transcript and protein levels when transfected in patient derived HD fibroblasts.

Results Here we show that the PS57 (CUG)7 AON can also reduce mutant ataxin 3 in a SCA3 patient cell line, and androgen receptor in an SBMA cell line.

Conclusions This suggests that PS57 could also be effective in other polyglutamine neurodegenerative diseases with a prolonged CAG repeat.

  • anitsense oligonucleotides
  • polyglutamine disorders
  • therapy

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