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L2 The expanded cag repeat in the huntingtin gene as target for therapeutic RNA modulation throughout the R6/2 and Q175 HD mouse brain
  1. Anchel González-Barriga1,
  2. Eleni Kourkouta1,
  3. Outi Kontkanen2,
  4. Taneli Heikkinen2,
  5. Kimmo Lehtimäki2,
  6. Judith CT van Deutekom1,
  7. Nicole A Datson1
  1. 1BioMarin Nederland BV, Leiden, The Netherlands
  2. 2Charles River Discovery Research Services, Kuopio, Finland


Background Different “huntingtin-lowering” therapeutic strategies based on RNA modulation are in early development for Huntington’s disease (HD).

Aims The aim of this study was to demonstrate the therapeutic potential of an antisense oligonucleotide (AON), with a (CUG)7 sequence targeting the CAG repeat in huntingtin (HTT) mRNA, in two different HD mouse models.

Methods/techniques The R6/2 HD N-terminal fragment mouse model was used to assess the extent of phenotypic reversal, while silencing duration of huntingtin mRNA and protein was investigated in the Q175 HD mouse knock-in model. Both R6/2 and Q175 mice received six weekly intracerebroventricular infusions with (CUG)7 or vehicle and were sacrificed between 2 weeks (R6/2) up to 18 weeks (Q175) post last infusion. Levels of mutant HTT mRNA and protein were quantified by RT-qPCR and TR-FRET respectively.

Results/outcome A highly significant and strong (~90%) reduction of mutant HTT mRNA levels was observed throughout the brain of (CUG)7-treated R6/2 mice, with a significant reduction of both soluble and aggregated mutant HTT protein in striatum, hippocampus and cortex. Furthermore, HTT-lowering increased whole brain and cortical volume and improved the performance of multiple motor tasks. In addition, reduced striatal levels of the gliosis marker myo-inositol were observed in (CUG)7-treated mice, along with increased mRNA levels of the striatal marker Darpp-32, a well-known integrator of dopamine signalling. These neuroanatomical and neurochemical changes, together with the improved motor performance, suggest that treatment with (CUG)7 ameliorates basal ganglia dysfunction.

In Q175 mice a long lasting effect of treatment with (CUG)7 was observed on soluble mutant HTT protein levels, with a reduction of at least 30% persisting up to 18 weeks post-treatment in cortex, striatum and hippocampus.

Conclusions These encouraging results support further preclinical development of the AON (CUG)7 as a therapeutic strategy for HD.

  • huntingtin-lowering
  • antisense oligonucleotide
  • therapy

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