Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington's disease patients.
Curr Biol
; 19(9): 774-8, 2009 May 12.
Article
en En
| MEDLINE
| ID: mdl-19361997
ABSTRACT
Among dominant neurodegenerative disorders, Huntington's disease (HD) is perhaps the best candidate for treatment with small interfering RNAs (siRNAs) [1-9]. Invariably fatal, HD is caused by expansion of a CAG repeat in the Huntingtin gene, creating an extended polyglutamine tract that makes the Huntingtin protein toxic [10]. Silencing mutant Huntingtin messenger RNA (mRNA) should provide therapeutic benefit, but normal Huntingtin likely contributes to neuronal function [11-13]. No siRNA strategy can yet distinguish among the normal and disease Huntingtin alleles and other mRNAs containing CAG repeats [14]. siRNAs targeting the disease isoform of a heterozygous single-nucleotide polymorphism (SNP) in Huntingtin provide an alternative [15-19]. We sequenced 22 predicted SNP sites in 225 human samples corresponding to HD and control subjects. We find that 48% of our patient population is heterozygous at a single SNP site; one isoform of this SNP is associated with HD. Several other SNP sites are frequently heterozygous. Consequently, five allele-specific siRNAs, corresponding to just three SNP sites, could be used to treat three-quarters of the United States and European HD patient populations. We have designed and validated selective siRNAs for the three SNP sites, laying the foundation for allele-specific RNA interference (RNAi) therapy for HD.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Proteínas Nucleares
/
Terapia Genética
/
Enfermedad de Huntington
/
Polimorfismo de Nucleótido Simple
/
ARN Interferente Pequeño
/
Interferencia de ARN
/
Proteínas del Tejido Nervioso
Límite:
Humans
Idioma:
En
Revista:
Curr Biol
Asunto de la revista:
BIOLOGIA
Año:
2009
Tipo del documento:
Article
País de afiliación:
Estados Unidos