B09 One antisense oligonucleotide as a potential therapy for polyglutamine disorders

Background To date there are nine known polyglutamine (polyQ) disorders: spinal bulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), Huntington9s 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 29OMePS 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.