Dominantly inherited polyglutamine disorders are chronic neurodegenerative diseases therapeutically amenable to gene-specific silencing strategies. Several compelling nucleic acid-based approaches have recently been developed to block the expression of mutant proteins and prevent toxic neurodegenerative sequelae. With such approaches, avoiding potential side effects caused by the concomitant ablation of the normal protein is an important objective. Therefore, allele-specific gene silencing is highly desirable; however, retaining wild type function is complex given that the common CAG mutation cannot be directly targeted, and might not be necessary or justifiable in all cases. Insights from polyglutamine gene function studies and the further development of allele-specific and other gene silencing methodologies will be important to determine the optimal therapeutic strategy for each polyglutamine disorder.
"One way to achieve this would be to enhance the degradation of mutant polyQ proteins through activation of the proteasome  or through upregulation of the autophagic pathway . Another strategy would be to inhibit the formation of mutant polyQ proteins by gene silencing or transcript degradation . RNAi is increasingly used as a potential therapeutic tool to reduce expression of target transcripts . "
[Show abstract][Hide abstract] ABSTRACT: To date there are 9 known diseases caused by an expanded polyglutamine repeat, with the most prevalent being Huntington's disease. Huntington's disease is a progressive autosomal dominant neurodegenerative disorder for which currently no therapy is available. It is caused by a CAG repeat expansion in the HTT gene, which results in an expansion of a glutamine stretch at the N-terminal end of the huntingtin protein. This polyglutamine expansion plays a central role in the disease and results in the accumulation of cytoplasmic and nuclear aggregates. Here, we make use of modified 2'-O-methyl phosphorothioate (CUG)n triplet-repeat antisense oligonucleotides to effectively reduce mutant huntingtin transcript and protein levels in patient-derived Huntington's disease fibroblasts and lymphoblasts. The most effective antisense oligonucleotide, (CUG)(7), also reduced mutant ataxin-1 and ataxin-3 mRNA levels in spinocerebellar ataxia 1 and 3, respectively, and atrophin-1 in dentatorubral-pallidoluysian atrophy patient derived fibroblasts. This antisense oligonucleotide is not only a promising therapeutic tool to reduce mutant huntingtin levels in Huntington's disease but our results in spinocerebellar ataxia and dentatorubral-pallidoluysian atrophy cells suggest that this could also be applicable to other polyglutamine expansion disorders as well.
PLoS ONE 09/2011; 6(9):e24308. DOI:10.1371/journal.pone.0024308 · 3.23 Impact Factor
"The lack of adequate therapies makes development of effective drugs a priority and innovative approaches will be necessary to identify safe and efficacious agents. One strategy for reducing levels of mutant genes is the use of synthetic antisense oligonucleotides or duplex RNAs to silence their expression (Denovan-Wright and Davidson, 2006; Gonzalez-Alegre and Paulson, 2007; Scholefield and Wood, 2010). These compounds are much larger than traditional small molecule drugs (-700 Da molecular mass), but advances in delivery protocols are making them a viable approach for developing drugs to treat neurological disease (Smith et al., 2006; De Souza et al., 2009). "
[Show abstract][Hide abstract] ABSTRACT: Spinocerebellar ataxia-3 (also known as Machado-Joseph disease) is an incurable neurodegenerative disorder caused by expression of a mutant variant of ataxin-3 (ATX3) pro-tein. Inhibiting expression of ATX3 would provide a thera-peutic strategy, but indiscriminant inhibition of both wild-type and mutant ATX3 might lead to undesirable side effects. An ideal silencing agent would block expression of mutant ATX3 while leaving expression of wild-type ATX3 intact. We have previously observed that peptide nucleic acid (PNA) conjugates targeting the expanded CAG repeat within ATX3 mRNA block expression of both alleles. We have now identified additional PNAs capable of inhibiting ATX3 expression that vary in length and in the nature of the con-jugated cation chain. We can also achieve potent and selec-tive inhibition using duplex RNAs containing one or more mismatches relative to the CAG repeat. Anti-CAG antisense bridged nucleic acid oligonucleotides that lack a cationic domain are potent inhibitors but are not allele-selective. Allele-selective inhibitors of ATX3 expression provide insights into the mechanism of selectivity and promising lead compounds for further development and in vivo investigation.
"The clinical severity of polyQ disorders, including SCA6, is linked both to the size of the polyQ expansion and to the expression level of the protein harboring the expansion (Williams and Paulson, 2008). Several groups including ours have used RNA interference (RNAi) (Scholefield and Wood, 2010) to target the expression of polyQ proteins. For several polyQ disorders, however, the use of RNAi as a clinical therapy will require preferential targeting of expanded polyQ proteins that minimally disrupts levels of wildtype , non-expanded polyQ protein. "
[Show abstract][Hide abstract] ABSTRACT: Spinocerebellar ataxia type 6 (SCA6) is an inherited neurodegenerative disease caused by a polyglutamine (polyQ) expansion in the Ca(V)2.1 voltage-gated calcium channel subunit (CACNA1A). There is currently no treatment for this debilitating disorder and thus a pressing need to develop preventative therapies. RNA interference (RNAi) has proven effective at halting disease progression in several models of spinocerebellar ataxia (SCA), including SCA types 1 and 3. However, in SCA6 and other dominantly inherited neurodegenerative disorders, RNAi-based strategies that selectively suppress expression of mutant alleles may be required. Using a Ca(V)2.1 mini-gene reporter system, we found that pathogenic CAG expansions in Ca(V)2.1 enhance splicing activity at the 3'end of the transcript, leading to a CAG repeat length-dependent increase in the levels of a polyQ-encoding Ca(V)2.1 mRNA splice isoform and the resultant disease protein. Taking advantage of this molecular phenomenon, we developed a novel splice isoform-specific (SIS)-RNAi strategy that selectively targets the polyQ-encoding Ca(V)2.1 splice variant. Selective suppression of transiently expressed and endogenous polyQ-encoding Ca(V)2.1 splice variants was achieved in a variety of cell-based models including a human neuronal cell line, using a new artificial miRNA-like delivery system. Moreover, the efficacy of gene silencing correlated with effective intracellular recognition and processing of SIS-RNAi miRNA mimics. These results lend support to the preclinical development of SIS-RNAi as a potential therapy for SCA6 and other dominantly inherited diseases.
Neurobiology of Disease 04/2011; 43(3):533-42. DOI:10.1016/j.nbd.2011.04.016 · 5.08 Impact Factor
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