Journal article
Broad Therapeutic Benefit After RNAi Expression Vector Delivery to Deep Cerebellar Nuclei: Implications for Spinocerebellar Ataxia Type 1 Therapy
Molecular therapy, Vol.22(3), pp.588-595
03/2014
DOI: 10.1038/mt.2013.279
PMCID: PMC3944323
PMID: 24419082
Abstract
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant, late-onset neurodegenerative disease caused by a polyglutamine (polyQ) expansion in the ataxin-1 protein, which causes progressive neurodegeneration in cerebellar Purkinje cells and brainstem nuclei. Here, we tested if reducing mutant ataxin-1 expression would significantly improve phenotypes in a knock-in (KI) mouse model that recapitulates spatial and temporal aspects of SCA1. Adeno-associated viruses (AAVs), expressing inhibitory RNAs targeting ataxin-1, were injected into the deep cerebellar nuclei (DCN) of KI mice. This approach induced ataxin-1 suppression in the cerebellar cortex and in brainstem neurons. RNA interference (RNAi) of ataxin-1 preserved cerebellar lobule integrity and prevented disease-related transcriptional changes for over a year. Notably, RNAi therapy also preserved rotarod performance and neurohistology. These data suggest that delivery of AAVs encoding RNAi sequences against ataxin-1, to DCN alone, may be sufficient for SCA1 therapy.
Details
- Title: Subtitle
- Broad Therapeutic Benefit After RNAi Expression Vector Delivery to Deep Cerebellar Nuclei: Implications for Spinocerebellar Ataxia Type 1 Therapy
- Creators
- Megan S Keiser - , Iowa City, IowaRyan L Boudreau - , Iowa City, IowaBeverly L Davidson - , Iowa City, Iowa
- Resource Type
- Journal article
- Publication Details
- Molecular therapy, Vol.22(3), pp.588-595
- Publisher
- Nature Publishing Group
- DOI
- 10.1038/mt.2013.279
- PMID
- 24419082
- PMCID
- PMC3944323
- ISSN
- 1525-0016
- eISSN
- 1525-0024
- Language
- English
- Date published
- 03/2014
- Academic Unit
- Iowa Neuroscience Institute; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984065488402771
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