Allele-specific silencing of dominant disease genes

Victor M Miller; Haibin Xia; Ginger L Marrs; Cynthia M Gouvion; Gloria Lee; Beverly L Davidson; Henry L Paulson

doi:10.1073/pnas.1231012100

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Allele-specific silencing of dominant disease genes

Journal article

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Allele-specific silencing of dominant disease genes

Victor M Miller, Haibin Xia, Ginger L Marrs, Cynthia M Gouvion, Gloria Lee, Beverly L Davidson and Henry L Paulson

Proceedings of the National Academy of Sciences - PNAS, Vol.100(12), pp.7195-7200

06/10/2003

DOI: 10.1073/pnas.1231012100

PMCID: PMC165852

PMID: 12782788

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Abstract

Small interfering RNA (siRNA) holds therapeutic promise for silencing dominantly acting disease genes, particularly if mutant alleles can be targeted selectively. In mammalian cell models we demonstrate that allele-specific silencing of disease genes with siRNA can be achieved by targeting either a linked single-nucleotide polymorphism (SNP) or the disease mutation directly. For a polyglutamine neurodegenerative disorder in which we first determined that selective targeting of the disease-causing CAG repeat is not possible, we took advantage of an associated SNP to generate siRNA that exclusively silenced the mutant Machado–Joseph disease/spinocerebellar ataxia type 3 allele while sparing expression of the WT allele. Allele-specific suppression was accomplished with all three approaches currently used to deliver siRNA: in vitro -synthesized duplexes as well as plasmid and viral expression of short hairpin RNA. We further optimized siRNA to specifically target a missense Tau mutation, V337M, that causes frontotemporal dementia. These studies establish that siRNA can be engineered to silence disease genes differing by a single nucleotide and highlight a key role for SNPs in extending the utility of siRNA in dominantly inherited disorders.

Biological Sciences

Details

Title: Subtitle: Allele-specific silencing of dominant disease genes
Creators: Victor M Miller - Department of Neurology
Haibin Xia - Department of Neurology
Ginger L Marrs - Department of Neurology
Cynthia M Gouvion - Department of Neurology
Gloria Lee - Department of Neurology
Beverly L Davidson - Department of Neurology
Henry L Paulson - Department of Neurology
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.100(12), pp.7195-7200
DOI: 10.1073/pnas.1231012100
PMID: 12782788
PMCID: PMC165852
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Language: English
Date published: 06/10/2003
Academic Unit: Iowa Neuroscience Institute; Immunology; Internal Medicine
Record Identifier: 9984065489202771

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