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

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.

SUBMITTER: Varela MA

PROVIDER: S-EPMC4717213 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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

Varela Miguel A MA Curtis Helen J HJ Douglas Andrew G L AG Hammond Suzan M SM O'Loughlin Aisling J AJ Sobrido Maria J MJ Scholefield Janine J Wood Matthew J A MJ

European journal of human genetics : EJHG 20150520 2

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 ...[more]

PMID: 25990798

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Project description:BACKGROUND:Cancer control programs have added patient navigation to improve effectiveness in underserved populations, but research has yielded mixed results about their impact on patient satisfaction. This study focuses on three related research questions in a U.S. state cancer screening program before and after a redesign that added patient navigators and services for chronic illness: Did patient diversity increase; Did satisfaction levels improve; Did socioeconomic characteristics or perceived barriers explain improved satisfaction. METHODS:Representative statewide patient samples were surveyed by phone both before and after the program design. Measures included satisfaction with overall health care and specific services, as well as experience of eleven barriers to accessing health care and self-reported health and sociodemographic characteristics. Multiple regression analysis is used to identify independent effects. RESULTS:After the program redesign, the percentage of Hispanic and African American patients increased by more than 200% and satisfaction with overall health care quality rose significantly, but satisfaction with the program and with primary program staff declined. Sociodemographic characteristics explained the apparent program effects on overall satisfaction, but perceived barriers did not. Further analysis indicates that patients being seen for cancer risk were more satisfied if they had a patient navigator. CONCLUSIONS:Health care access can be improved and patient diversity increased in public health programs by adding patient navigators and delivering more holistic care. Effects on patient satisfaction vary with patient health needs, with those being seen for chronic illness likely to be less satisfied with their health care than those being seen for cancer risk. It is important to use appropriate comparison groups when evaluating the effect of program changes on patient satisfaction and to consider establishing appropriate satisfaction benchmarks for patients being seen for chronic illness.

Dataset Information

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

Publications

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

Similar Datasets

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