Self-duplexing CUG repeats selectively inhibit mutant huntingtin expression

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Self-duplexing CUG repeats selectively inhibit mutant huntingtin expression

Huntington's disease (HD) is a neurodegenerative genetic disorder caused by the expansion of the CAG repeat in the translated sequence of the HTT gene. This expansion generates a mutant huntingtin protein that contains an abnormally elongated polyglutamine tract, which, together with mutant transcript, causes cellular dysfunction. Currently, there is no curative treatment available to patients ...

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Single-Stranded RNAs Use RNAi to Potently and Allele-Selectively Inhibit Mutant Huntingtin Expression

Mutant huntingtin (HTT) protein causes Huntington disease (HD), an incurable neurological disorder. Silencing mutant HTT using nucleic acids would eliminate the root cause of HD. Developing nucleic acid drugs is challenging, and an ideal clinical approach to gene silencing would combine the simplicity of single-stranded antisense oligonucleotides with the efficiency of RNAi. Here, we describe R...

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Inhibition of mutant huntingtin expression by RNA duplex targeting expanded CAG repeats

The specific silencing of the gene of interest is the major objective of RNA interference technology; therefore, unique sequences but not abundant sequence repeats are targeted by silencing reagents. Here, we describe the targeting of expanded CAG repeats that occur in transcripts derived from the mutant allele of the gene implicated in Huntington's disease (HD) in the presence of the normal al...

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A simple ligand that selectively targets CUG trinucleotide repeats and inhibits MBNL protein binding.

This work describes the rational design, synthesis, and study of a ligand that selectively complexes CUG repeats in RNA (and CTG repeats in DNA) with high nanomolar affinity. This sequence is considered a causative agent of myotonic dystrophy type 1 (DM1) because of its ability to sequester muscleblind-like (MBNL) proteins. Ligand 1 was synthesized in two steps from commercially available compo...

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ژورنال

عنوان ژورنال: Nucleic Acids Research

سال: 2013

ISSN: 1362-4962,0305-1048

DOI: 10.1093/nar/gkt825