ArticleMolecular therapy. Nucleic acids2026
An acyclic nucleic acid-modified siRNA targeting CAG expansions for polyglutamine disease treatment.
Article in Molecular therapy. Nucleic acids, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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2 citing papers in PubMed.
- Acyclic artificial nucleic acid substitution expands the safe design space of gapmer ASOs by preventing P54nrb mislocalization.NAR molecular medicine · 2026Article
- Selective silencing of expanded CAG repeats: Chemically modified siRNA advances RNA-based therapies for polyglutamine diseases.Molecular therapy. Nucleic acids · 2026Article
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12 authors.
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Abstract
Polyglutamine (polyQ) diseases are inherited neurological disorders caused by an expansion of the cytosine-adenine-guanine (CAG) repeat in the causative genes. These include Huntington's disease, spinal and bulbar muscular atrophy (SBMA), and spinocerebellar ataxias (SCAs). Clinical trials have been conducted using nucleic acid therapeutics to silence the causative gene for these diseases, but none have been approved for use. Furthermore, while oligonucleotides targeting the CAG repeats are an attractive therapeutic option, concomitant silencing of the wild-type allele with normal CAG repeats can result in neuronal dysfunction. In this study, we developed an acyclic serinol nucleic acid (SNA)-modified small interfering RNA (siRNA) targeting CAG repeats. We also evaluated the safety and efficacy of the siRNA in different mouse models of polyQ diseases. Intracerebroventricularly administered siRNA was widely distributed throughout the central nervous system, where it selectively silenced the alleles encoding polyQ proteins without affecting their wild-type counterparts. Consequently, the intranuclear aggregation of polyQ proteins was reduced in mouse models of SBMA and SCA type 3. The siRNA attenuated neuromuscular degeneration and improved the lifespan and motor function of the SBMA mice. These findings suggest that SNA-modified siRNAs targeting CAG repeats represent a promising approach for treating polyQ diseases.
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