Therapeutic gene silencing strategies for polyglutamine disorders.
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.
SourceAvailable from: Jyoti B Chattopadhyaya[Show abstract] [Hide abstract]
ABSTRACT: Several novel nucleoside analogues as potential inhibitors of glycosidases and purine nucleoside phosphorylase (PNP) have been synthesized via selective coupling of an appropriate nucleobase at different positions of an orthogonally protected imino sugar as a common precursor. This synthetic strategy offers a straightforward protocol for the assembly of imino sugar containing nucleosides, establishing a new repertoire of molecules as potential therapeutics.The Journal of Organic Chemistry 05/2012; 77(10):4671-8. DOI:10.1021/jo3004452 · 4.64 Impact Factor
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ABSTRACT: Polyglutamine neurodegenerative diseases result from the expansion of a trinucleotide CAG repeat, encoding a polyglutamine tract in the disease-causing protein. The process by which each polyglutamine protein exerts its toxicity is complex, involving a variety of mechanisms including transcriptional dysregulation, proteasome impairment and mitochondrial dysfunction. Thus, the most effective and widely applicable therapies are likely to be those designed to eliminate production of the mutant protein upstream of these deleterious effects. RNA-based approaches represent promising therapeutic strategies for polyglutamine diseases, offering the potential to suppress gene expression in a sequence-specific manner at the transcriptional and post-transcriptional levels. In particular, gene silencing therapies capable of discrimination between mutant and wildtype alleles, based on disease-linked polymorphisms or CAG repeat length, might prove crucial in cases where a loss of wild type function is deleterious. Novel methods, such as gene knockdown and replacement, seek to eliminate the technical difficulties associated with allele-specific silencing by avoiding the need to target specific mutations. With a variety of RNA technologies currently being developed to target multiple facets of polyglutamine pathogenesis, the emergence of an effective therapy seems imminent. However, numerous technical obstacles associated with design, discrimination and delivery must be overcome before RNA therapy can be effectively applied in the clinical setting.Expert Reviews in Molecular Medicine 01/2012; 14:e3. DOI:10.1017/erm.2011.1 · 5.91 Impact Factor
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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.Biological Chemistry 05/2011; 392:315-325. DOI:10.1515/BC.2011.045 · 2.69 Impact Factor