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Transfer of genetic therapy across human populations: molecular targets for increasing patient coverage in repeat expansion diseases

Transfer of genetic therapy across human populations: molecular targets for increasing patient coverage in repeat expansion diseases
Transfer of genetic therapy across human populations: molecular targets for increasing patient coverage in repeat expansion diseases
Allele-specific gene therapy aims to silence expression of mutant alleles through targeting of disease-linked single-nucleotide polymorphisms (SNPs). However, SNP linkage to disease varies between populations, making such molecular therapies applicable only to a subset of patients. Moreover, not all SNPs have the molecular features necessary for potent gene silencing. Here we provide knowledge to allow the maximisation of patient coverage by building a comprehensive understanding of SNPs ranked according to their predicted suitability toward allele-specific silencing in 14 repeat expansion diseases: amyotrophic lateral sclerosis and frontotemporal dementia, dentatorubral-pallidoluysian atrophy, myotonic dystrophy 1, myotonic dystrophy 2, Huntington’s disease and several spinocerebellar ataxias. Our systematic analysis of DNA sequence variation shows that most annotated SNPs are not suitable for potent allele-specific silencing across populations because of suboptimal sequence features and low variability (>97% in HD). We suggest maximising patient coverage by selecting SNPs with high heterozygosity across populations, and preferentially targeting SNPs that lead to purine:purine mismatches in wild-type alleles to obtain potent allele-specific silencing. We therefore provide fundamental knowledge on strategies for optimising patient coverage of therapeutics for microsatellite expansion disorders by linking analysis of population genetic variation to the selection of molecular targets.
1018-4813
271-276
Varela, Miguel A.
2dc5ecd9-fa40-4f5c-b748-ec368ec02497
Curtis, Helen J.
058ada04-e721-4125-9667-2b80c7ae2ffa
Douglas, Andrew G.L.
2c789ec4-a222-43bc-a040-522ca64fea42
Hammond, Suzan M.
989e8c8c-2d56-46a3-8c25-26924a510d58
O'Loughlin, Aisling J.
488e0a37-b7bd-4708-9b11-2831533d5c45
Sobrido, Maria J.
01c3077a-8f22-4509-82e9-7ee0518807c4
Scholefield, Janine
047c8e01-73fa-4c45-bad4-156ff7f6b8b4
Wood, Matthew J.A.
2dd0c89e-a284-4012-a125-72b883df6af8
Varela, Miguel A.
2dc5ecd9-fa40-4f5c-b748-ec368ec02497
Curtis, Helen J.
058ada04-e721-4125-9667-2b80c7ae2ffa
Douglas, Andrew G.L.
2c789ec4-a222-43bc-a040-522ca64fea42
Hammond, Suzan M.
989e8c8c-2d56-46a3-8c25-26924a510d58
O'Loughlin, Aisling J.
488e0a37-b7bd-4708-9b11-2831533d5c45
Sobrido, Maria J.
01c3077a-8f22-4509-82e9-7ee0518807c4
Scholefield, Janine
047c8e01-73fa-4c45-bad4-156ff7f6b8b4
Wood, Matthew J.A.
2dd0c89e-a284-4012-a125-72b883df6af8

Varela, Miguel A., Curtis, Helen J., Douglas, Andrew G.L., Hammond, Suzan M., O'Loughlin, Aisling J., Sobrido, Maria J., Scholefield, Janine and Wood, Matthew J.A. (2016) Transfer of genetic therapy across human populations: molecular targets for increasing patient coverage in repeat expansion diseases. European Journal of Human Genetics, 24 (2), 271-276. (doi:10.1038/ejhg.2015.94).

Record type: Article

Abstract

Allele-specific gene therapy aims to silence expression of mutant alleles through targeting of disease-linked single-nucleotide polymorphisms (SNPs). However, SNP linkage to disease varies between populations, making such molecular therapies applicable only to a subset of patients. Moreover, not all SNPs have the molecular features necessary for potent gene silencing. Here we provide knowledge to allow the maximisation of patient coverage by building a comprehensive understanding of SNPs ranked according to their predicted suitability toward allele-specific silencing in 14 repeat expansion diseases: amyotrophic lateral sclerosis and frontotemporal dementia, dentatorubral-pallidoluysian atrophy, myotonic dystrophy 1, myotonic dystrophy 2, Huntington’s disease and several spinocerebellar ataxias. Our systematic analysis of DNA sequence variation shows that most annotated SNPs are not suitable for potent allele-specific silencing across populations because of suboptimal sequence features and low variability (>97% in HD). We suggest maximising patient coverage by selecting SNPs with high heterozygosity across populations, and preferentially targeting SNPs that lead to purine:purine mismatches in wild-type alleles to obtain potent allele-specific silencing. We therefore provide fundamental knowledge on strategies for optimising patient coverage of therapeutics for microsatellite expansion disorders by linking analysis of population genetic variation to the selection of molecular targets.

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More information

Accepted/In Press date: 31 March 2015
e-pub ahead of print date: 20 May 2015
Published date: February 2016
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 394072
URI: http://eprints.soton.ac.uk/id/eprint/394072
ISSN: 1018-4813
PURE UUID: 477d7b4b-021d-427b-a2b3-14f684bf9028
ORCID for Andrew G.L. Douglas: ORCID iD orcid.org/0000-0001-5154-6714

Catalogue record

Date deposited: 11 May 2016 09:23
Last modified: 22 Oct 2019 00:39

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Contributors

Author: Miguel A. Varela
Author: Helen J. Curtis
Author: Suzan M. Hammond
Author: Aisling J. O'Loughlin
Author: Maria J. Sobrido
Author: Janine Scholefield
Author: Matthew J.A. Wood

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