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ASO corrects striatal transcriptional abnormalities & protects function in HD mice
Date:8/26/2013

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The investigators used the YAC 128 mouse HD model, which mimics many of the pathologic hallmarks of human HD. These include age-related loss of brain mass and a regionally distinct pattern of mutant HTT accumulation.

They found that levels of several striatal mRNAs (DARPP-32, DIR, D2R, Enk and CB1) progressively decreased with age in the YAC128 mice but no age-related changes were seen in the controls. Significant differences between the groups were found at 9 and 12 months. "Transcriptional dysregulation in the YAC128 HD mouse does not appear to be a phenomenon of accelerated aging but likely of the disease process," says Dr. Stanek.

Investigators focused on whether an ASO directed against mutant HTT mRNA could be an effective therapeutic strategy. ASO or saline was administered directly into the CNS via an intraventricular cannula for two weeks using an osmotic mini pump. After a two-week recovery, the mice were tested on an accelerating rotarod apparatus to measure their motor coordination and motor learning, and then on the Porsolt swim test which is used to assess depression in rodents. Two to four months after ASO treatment began, ASO-treated YAC128 mice continued to perform at the same level as saline-treated wild type controls, while age-matched saline-treated YAC128 mice performed significantly worse. In other words, the ASO treatment prevented a decline in motor coordination. Similarly, the ASO treatment lessened the onset of depressive behavior, as measured by immobility during the swim test, in these HD mutant mice.

When the mouse brains were analyzed, the ASO-treated YAC128 mice showed a 30% reduction in mutant HTT mRNA levels and significant reduction in mutant HTT protein levels four months after the start of ASO treatment. Thus, the study showed a correlation between the correction of transcriptional abnormalities and functional improvement.

Further experimentation focused on the effect of ASO treat
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Contact: Daphne Watrin
d.watrin@iospress.nl
31-206-883-355
IOS Press
Source:Eurekalert

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