Personalized gene silencing therapeutics for Huntington disease
- 11 April 2014
- journal article
- review article
- Published by Wiley in Clinical Genetics
- Vol. 86 (1), 29-36
- https://doi.org/10.1111/cge.12385
Abstract
Gene silencing offers a novel therapeutic strategy for dominant genetic disorders. In specific diseases, selective silencing of only one copy of a gene may be advantageous over non-selective silencing of both copies. Huntington disease (HD) is an autosomal dominant disorder caused by an expanded CAG trinucleotide repeat in the Huntingtin gene (HTT). Silencing both expanded and normal copies of HTT may be therapeutically beneficial, but preservation of normal HTT expression is preferred. Allele-specific methods can selectively silence the mutant HTT transcript by targeting either the expanded CAG repeat or single nucleotide polymorphisms (SNPs) in linkage disequilibrium with the expansion. Both approaches require personalized treatment strategies based on patient genotypes. We compare the prospect of safe treatment of HD by CAG- and SNP-specific silencing approaches and review HD population genetics used to guide target identification in the patient population. Clinical implementation of allele-specific HTT silencing faces challenges common to personalized genetic medicine, requiring novel solutions from clinical scientists and regulatory authorities.Keywords
This publication has 48 references indexed in Scilit:
- Single-Stranded RNAs Use RNAi to Potently and Allele-Selectively Inhibit Mutant Huntingtin ExpressionCell, 2012
- Sustained Therapeutic Reversal of Huntington's Disease by Transient Repression of Huntingtin SynthesisNeuron, 2012
- Common SNP-Based Haplotype Analysis of the 4p16.3 Huntington Disease Gene RegionAmerican Journal of Human Genetics, 2012
- Potent and Selective Antisense Oligonucleotides Targeting Single-Nucleotide Polymorphisms in the Huntington Disease Gene / Allele-Specific Silencing of Mutant HuntingtinMolecular Therapy, 2011
- HTT haplotypes contribute to differences in Huntington disease prevalence between Europe and East AsiaEuropean Journal of Human Genetics, 2011
- Allele-Selective Inhibition of Mutant Huntingtin Expression with Antisense Oligonucleotides Targeting the Expanded CAG RepeatBiochemistry, 2010
- Novel RNA-based Strategies for Therapeutic Gene SilencingMolecular Therapy, 2010
- A majority of Huntington's disease patients may be treatable by individualized allele-specific RNA interferenceExperimental Neurology, 2009
- Five siRNAs Targeting Three SNPs May Provide Therapy for Three-Quarters of Huntington's Disease PatientsCurrent Biology, 2009
- CAG Expansion in the Huntington Disease Gene Is Associated with a Specific and Targetable Predisposing HaplogroupAmerican Journal of Human Genetics, 2009