Spinocerebellar Ataxia Type 1 (SCA1) is an autosomal dominant late onset neurodegenerative disease caused by an expanded polyglutamine tract in ataxin-1. Here, we compared the protective effects of overexpressing ataxin-1-like using recombinant AAVs, or reducing expression of mutant ataxin-1 using virally delivered RNA interference (RNAi), in a transgenic mouse model of SCA1. For the latter, we used an artificial microRNA (miR) design that optimizes potency, efficacy and safety to suppress ataxin-1 expression (miS1). Delivery of either ataxin-1-like or miS1 viral vectors to SCA1 mice cerebella resulted in widespread cerebellar Purkinje cell transduction and improved behavioral and histological phenotypes. Our data indicate the utility of either approach as a possible therapy for SCA1 patients.
"We designed small interfering RNAs (siRNAs) targeting ataxin-7 using a low off-target prediction algorithm . These siRNAs were cloned into artificial miRNA expression vectors  and were tested in vitro. "
[Show abstract][Hide abstract] ABSTRACT: Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disease characterized by loss of motor coordination and retinal degeneration with no current therapies in the clinic. The causative mutation is an expanded CAG repeat in the ataxin-7 gene whose mutant protein product causes cerebellar and brainstem degeneration and retinal cone-rod dystrophy. Here, we reduced the expression of both mutant and wildtype ataxin-7 in the SCA7 mouse retina by RNA interference and evaluated retinal function 23 weeks post injection. We observed a preservation of normal retinal function and no adverse toxicity with ≥50% reduction of mutant and wildtype ataxin-7 alleles. These studies address an important safety concern regarding non-allele specific silencing of ataxin-7 for SCA7 retinal therapy.
PLoS ONE 04/2014; 9(4):e95362. DOI:10.1371/journal.pone.0095362 · 3.23 Impact Factor
[Show abstract][Hide abstract] 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.Molecular Therapy (2014); doi:10.1038/mt.2013.279.
[Show abstract][Hide abstract] ABSTRACT: Considerable advances have been recently made in understanding the molecular aspects of pathogenesis and in developing therapeutic
approaches for polyglutamine (polyQ) diseases. Studies on pathogenic mechanisms have extended our knowledge of mutant protein
toxicity, confirmed the toxicity of mutant transcript and identified other toxic RNA and protein entities. One very promising
therapeutic strategy is targeting the causative gene expression with oligonucleotide (ON) based tools. This straightforward
approach aimed at halting the early steps in the cascade of pathogenic events has been widely tested for Huntington's disease
and spinocerebellar ataxia type 3. In this review, we gather information on the use of antisense oligonucleotides and RNA
interference triggers for the experimental treatment of polyQ diseases in cellular and animal models. We present studies testing
non-allele-selective and allele-selective gene silencing strategies. The latter include targeting SNP variants associated
with mutations or targeting the pathologically expanded CAG repeat directly. We compare gene silencing effectors of various
types in a number of aspects, including their design, efficiency in cell culture experiments and pre-clinical testing. We
discuss advantages, current limitations and perspectives of various ON-based strategies used to treat polyQ diseases.
Nucleic Acids Research 05/2014; 42(11). DOI:10.1093/nar/gku385 · 9.11 Impact Factor
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