Nonallele-specific Silencing of Mutant and Wild-type Huntingtin Demonstrates Therapeutic Efficacy in Huntington's Disease Mice

Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52240, USA.
Molecular Therapy (Impact Factor: 6.23). 03/2009; 17(6):1053-63. DOI: 10.1038/mt.2009.17
Source: PubMed


Huntington's disease (HD) is a fatal neurodegenerative disease caused by mutant huntingtin (htt) protein, and there are currently no effective treatments. Recently, we and others demonstrated that silencing mutant htt via RNA interference (RNAi) provides therapeutic benefit in HD mice. We have since found that silencing wild-type htt in adult mouse striatum is tolerated for at least 4 months. However, given the role of htt in various cellular processes, it remains unknown whether nonallele-specific silencing of both wild-type and mutant htt is a viable therapeutic strategy for HD. Here, we tested whether cosilencing wild-type and mutant htt provides therapeutic benefit and is tolerable in HD mice. After treatment, HD mice showed significant reductions in wild-type and mutant htt, and demonstrated improved motor coordination and survival. We performed transcriptional profiling to evaluate the effects of reducing wild-type htt in adult mouse striatum. We identified gene expression changes that are concordant with previously described roles for htt in various cellular processes. Also, several abnormally expressed transcripts associated with early-stage HD were differentially expressed in our studies, but intriguingly, those involved in neuronal function changed in opposing directions. Together, these encouraging and surprising findings support further testing of nonallele-specific RNAi therapeutics for HD.

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    • "Animal models of idiopathic Parkinson's disease have been extensively treated by protection of dopaminergic neurons through overexpression of trophic factors (GDNF) in the substantia nigra [17] [18] [19] or alternatively through expression of enzymes for dopamine synthesis in surviving cells of the striatum [3] or GABA in the subthalamic nucleus [20]. In Huntington's diseases models, although a trophic approach has also been extensively explored [21], a more precise line aimed at silencing the mutant Huntingtin gene in the GABAergic medium spiny neurons of the striatum was explored [22] [23] [24]. As for these and other prototypical gene therapy approaches, the modeled disease could be slowed they subsequently have been, or are being, progressively scaled-up for translational therapies in humans [3] [20]. "
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    • "There are some studies conducted in HD mouse models that support the idea that reducing both wt and mHTT is well tolerated and leads to clinical benefit [20]–[23]. However, alterations in molecular pathways associated with loss of normal HTT function have also been observed [24], [25]. It is very difficult to predict how these findings may translate into human applications. "
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