Modified RNAi agents
Inventors
Rajeev, Kallanthottathil G. • Zimmermann, Tracy • Manoharan, Muthiah • Maier, Martin • KUCHIMANCHI, Satyanarayana • Charisse, Klaus
Assignees
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Publication Number
US-12290573-B2
Publication Date
2025-05-06
Expiration Date
Abstract
One aspect of the present invention relates to double-stranded RNAi (dsRNA) duplex agent capable of inhibiting the expression of a target gene. The dsRNA duplex comprises one or more motifs of three identical modifications on three consecutive nucleotides in one or both strand, particularly at or near the cleavage site of the strand. Other aspects of the invention relates to pharmaceutical compositions comprising these dsRNA agents suitable for therapeutic use, and methods of inhibiting the expression of a target gene by administering these dsRNA agents, e.g., for the treatment of various disease conditions.
Core Innovation
The invention relates to a double-stranded RNAi agent capable of inhibiting the expression of a target gene, comprising a sense strand and an antisense strand. Each strand has 14 to 30 nucleotides, and the sense strand sequence is defined by formula (I) with specified parameters for strand blocks and overhang nucleotides.
The sense strand structure includes motifs of three identical modifications on three consecutive nucleotides, with the YYY motif consisting of three 2′-F modified nucleotides occurring at positions 9, 10 and 11 of the sense strand from the 5′-end. The nucleotide next to a XXX, YYY or ZZZ motif uses a different modification than the modification of the motif, and at least one of the sense strand and antisense strand contains at least one phosphorothioate internucleotide modification within the first 5 nucleotides, counting from the 5′-end of the strand.
The duplex design supports modified siRNA duplexes for gene-silencing activity and target gene expression inhibition, including optional multimeric constructs, optional wing modifications, and optional ligand conjugation. The document further describes pharmaceutical compositions and disease-treatment methods using the modified double-stranded RNAi agent, including administration by subcutaneous or intravenous routes.
Claims Coverage
The consolidated claim coverage includes one independent claim directed to a double-stranded RNAi agent with three inventive features centered on motif-defined modification architecture, strand/duplex length and formula constraints, and phosphorothioate placement.
Double-stranded RNAi agent with defined sense-strand formula and motif-based modification architecture
A double-stranded RNAi agent capable of inhibiting expression of a target gene, comprising a sense strand and an antisense strand, each having 14 to 30 nucleotides, where the sense strand sequence is represented by formula (I) with specified parameters for motif blocks, overhang nucleotide(s), and motif-defined modified nucleotides.
Placed 2′-F motif with alternating different nucleotide modifications adjacent to motifs
The sense strand modification pattern specifies that YYY represents three 2′-F modified nucleotides and that the YYY motif occurs at positions 9, 10 and 11 of the sense strand from the 5′-end, with the nucleotide next to a XXX, YYY or ZZZ motif having a different modification than the modification of the motif itself.
Phosphorothioate internucleotide modification within first 5 nucleotides
At least one of the sense strand and antisense strand contains at least one phosphorothioate internucleotide modification within the first 5 nucleotides, counting from the 5′-end of the strand.
Overall, the claims center on a modified siRNA duplex architecture defined by sense-strand formula (I), a specific YYY 2′-F motif placement at positions 9–11, adjacent-difference modification constraints, and the presence of a phosphorothioate internucleotide modification within the first 5 nucleotides of at least one strand.
Stated Advantages
Relative cleavage-rate advantages in target cells versus serum.
Inhibits the expression of a target gene.
Documented Applications
Pharmaceutical compositions and disease-treatment methods using the modified double-stranded RNAi agent.
Use in pharmaceutical compositions with defined routes of delivery including intravenous and subcutaneous administration.
In vitro screening of modified siRNA duplexes with IC50 testing, including TTR siRNA and ANGPTL3 modified duplex embodiments [procedural detail omitted for safety].
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