Double-stranded nucleic acid inhibitor molecules with shortened sense strands
Inventors
Brown, Bob Dale • Wang, Weimin • Nazef, Naim
Assignees
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Publication Number
US-12529053-B2
Publication Date
2026-01-20
Expiration Date
Abstract
Provided herein are double-stranded nucleic acid inhibitor molecules having a shortened sense strand with a stem loop structure and an antisense strand. Also provided are methods and compositions for reducing target gene expression and methods and compositions for treating a disease of interest.
Core Innovation
The invention provides a double-stranded nucleic acid inhibitor molecule having a sense strand and an antisense strand as separate strands, with defined nucleotide lengths. The sense strand comprises a first region (R1) and a second region (R2), and the molecule forms a first duplex (D1) from the first region of the sense strand and the antisense strand, with a defined length of 8-29 base pairs.
In the sense strand, the second region (R2) comprises a first subregion (S1), a second subregion (S2), and a single stranded loop joining S1 and S2. The first and second subregions form a second duplex (D2), where the second duplex has a defined length of 3-5 base pairs and comprises at least one bicyclic nucleotide.
The antisense strand has a single stranded overhang of 7-9 nucleotides at the 3′-end. The invention further defines alternative structural options that include bicyclic nucleotide placement in the antisense strand overhang context and the second duplex (D2), including an option where nucleotide 1 of the sense strand is a bicyclic nucleotide.
Claims Coverage
The independent claim defines a double-stranded nucleic acid inhibitor molecule with sense/antisense strand length ranges, two duplex structures (D1 and D2), a single stranded loop in the sense second region (R2), a 3′-end antisense overhang, and a bicyclic nucleotide requirement in the second duplex. The inventive core is specified through quantified structural features for duplex lengths, overhang length, and bicyclic nucleotide content/placement.
Double-stranded inhibitor with defined sense and antisense lengths
A double-stranded nucleic acid inhibitor molecule comprising a sense strand having 15-43 nucleotides with a first region (R1) and a second region (R2), and an antisense strand having 18-35 nucleotides with 5′- and 3′-ends, where the sense strand and antisense strand are separate strands.
First duplex formation with defined length
A first duplex (D1) formed by the first region (R1) of the sense strand and the antisense strand, where the first duplex has a length of 8-29 base pairs.
Sense second region loop forming a second duplex
The second region (R2) comprises a first subregion (S1), a second subregion (S2), and a single stranded loop that joins the first and second subregions, where the first and second subregions form a second duplex (D2).
3′ overhang and bicyclic nucleotide requirement in second duplex
The antisense strand has a single stranded overhang of 7-9 nucleotides at the 3′-end and the second duplex has a length of 3-5 base pairs and comprises at least one bicyclic nucleotide; or the antisense strand has a single stranded overhang of 7-9 nucleotides at the 3′-end, nucleotide 1 of the sense strand is a bicyclic nucleotide, and the second duplex has a length of 3-5 base pairs and comprises at least one bicyclic nucleotide.
Overall claim coverage centers on a structured double-stranded nucleic acid inhibitor with two duplexes (D1 and D2), where D2 includes at least one bicyclic nucleotide and has a defined 3-5 base-pair length, together with quantified sense/antisense lengths, a single stranded loop in the sense second region, and a 3′-end antisense overhang.
Stated Advantages
Maintains potency when shortening the 5′-end of the sense strand.
Stabilizes molecules using Tm-increasing nucleotides and/or antisense internucleotide modifications.
Improves in vivo mRNA knockdown duration.
Documented Applications
Reducing target gene expression by administering the inhibitor/composition to subjects including humans, with routes including IV, IM, and SC.
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