Therapeutic gene silencing strategies for polyglutamine disorders.

Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX13QX, UK.
Trends in Genetics (Impact Factor: 11.6). 12/2009; 26(1):29-38. DOI: 10.1016/j.tig.2009.11.005
Source: PubMed

ABSTRACT 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.

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    • "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). "
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    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.
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    • "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. "
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