Compositions and methods for enhancing discriminatory RNA interference
First Claim
1. A method of enhancing discriminatory RNA silencing by an RNA silencing agent comprising positioning a specificity-determining nucleotide of said agent at a nucleotide position within an antisense strand of said agent, wherein the nucleotide position is 3′
- of the seed sequence of said antisense strand, such that discriminatory RNA silencing is enhanced.
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Abstract
The present invention provides methods for enhancing discriminatory RNA silencing by RNA silencing agents. In particular, the invention provides methods for generating RNA silencing agents which can discriminate between target and non-target mRNAs that differ in sequence by only one nucleotide. Also provided are improved RNA silencing agents with enhanced discriminatory RNA silencing, e.g., single nucleotide discriminatory RNA silencing. The compositions and methods of the invention are useful in therapeutic strategies for treating genetic disorders associated with dominant, gain-of-function gene mutations.
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Citations
42 Claims
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1. A method of enhancing discriminatory RNA silencing by an RNA silencing agent comprising positioning a specificity-determining nucleotide of said agent at a nucleotide position within an antisense strand of said agent, wherein the nucleotide position is 3′
- of the seed sequence of said antisense strand, such that discriminatory RNA silencing is enhanced.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 32, 39, 40, 41)
- 19. A method of enhancing discriminatory RNA silencing by an RNA silencing agent comprising substituting at least one nucleotide within an antisense strand of said agent with a destabilizing nucleotide, such that discriminatory RNA silencing by said RNA silencing agent is enhanced.
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42. A method of enhancing discriminatory RNA silencing by an RNA silencing agent comprising positioning a specificity-determining nucleotide of said agent at nucleotide position P10 or P 16 relative to the 5′
- end of an antisense strand of said agent, wherein (i) the nucleotide position is 3′
of the seed sequence of said antisense strand, (ii) the specificity-determining nucleotide forms a purine;
purine mismatch with a non-target mRNA; and
(iii) the specificity-determining nucleotide forms a Watson-Crick base pair with a target mRNA, such that discriminatory RNA silencing is enhanced.
- end of an antisense strand of said agent, wherein (i) the nucleotide position is 3′
Specification