Abstract
Trinucleotide repeats are responsible for many genetic diseases. Previous studies have shown that duplex RNAs (dsRNAs) can be used to target expression of a mutant repeat allele while leaving expression of the wild-type allele untouched, creating opportunities for allele-selective inhibition and better therapeutic outcomes. In contrast to successes with other genes, we report here that we cannot achieve allele-selective inhibition when targeting the expanded CAG repeat within Ataxin-1 (ATXN1), the cause of spinal cerebellar ataxia-1 (SCA1). The most likely explanation for this unfavorable outcome is that the mean CAG repeat number within wild-type ATXN1 is relatively high compared to other trinucleotide repeat diseases. Because the wild-type repeat number is high, it is likely that there is poor discrimination between the mutant and wild-type repeat and less opportunity for allele-selective inhibition across the entire spectrum of mutations found in SCA1 patients. Our data support the conclusion that the potential for multiple cooperative binding interactions is a critical factor governing allele-selective recognition of trinucleotide repeat genes by duplex RNAs. These results should be helpful in predicting which diseases and which patients are most likely to benefit from allele-selective targeting of expanded repeats.
Original language | English (US) |
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Pages (from-to) | 185-194 |
Number of pages | 10 |
Journal | Nucleosides, Nucleotides and Nucleic Acids |
Volume | 39 |
Issue number | 1-3 |
DOIs | |
State | Published - Feb 20 2020 |
Keywords
- Duplex RNA
- RNAi
- allele-selective inhibition
- ataxin-1 (ATXN1)
- spinal cerebellar ataxia-1 (SCA1)
- trinucleotide repeat
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Genetics