Coronavirus IRNA compositions and methods of use thereof
Inventors
Akinc, Akin • McIninch, James D. • Anglero-Rodriguez, Yesseinia • Schlegel, Mark K. • Hebner, Christy M. • LEMPP, Florian A.
Assignees
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Publication Number
US-12391945-B2
Publication Date
2025-08-19
Expiration Date
Abstract
The present invention relates to RNAi agents, e.g., dsRNA agents, targeting the coronavirus genome. The invention also relates to methods of using such RNAi agents to inhibit expression of a coronavirus genome and to methods of treating or preventing a coronavirus-associated disease in a subject.
Core Innovation
The invention relates to coronavirus-targeting double stranded ribonucleic acid (dsRNA) agents for inhibiting expression of a coronavirus genome in a cell, or salts thereof. The dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, and the antisense strand includes a nucleotide sequence that differs by no more than three bases from specified antisense strand nucleotide sequences selected from SEQ ID NO:586, SEQ ID NO:719, and SEQ ID NO:1852.
The disclosure describes sequence relationships and structural features for antisense targeting of coronavirus mRNA and/or genome through RNA interference (RNAi), including via the RISC pathway to inhibit coronavirus genome expression and replication. It further emphasizes enhanced in vivo activity by chemical and conjugation modifications, including one or more lipophilic moieties comprising a saturated or unsaturated C16 hydrocarbon chain, 5′ phosphate or phosphate mimics including 5′-vinyl phosphonate, and optional liver-targeting ligand incorporation such as GalNAc.
The disclosed dsRNA agents include controlled structural and chemical modification features positioned around the double stranded region and relative to Dicer cleavage, together with defined end structures including overhangs, blunt ends, and asymmetric ends for RISC loading. The disclosure also includes carbohydrate-linked iRNA/dsRNA conjugates in which an RNAi agent is attached to a carbohydrate conjugate via a linker, including GalNAc and GalNAc derivatives with cleavable or non-cleavable linkers.
Claims Coverage
The provided claim content centers on one independent claim directed to a dsRNA agent for inhibiting expression of a coronavirus genome in a cell. The core inventive features are the dsRNA duplex structure and the antisense sequence constraint defined relative to selected reference antisense sequences, with additional dependent features covering end modifications, lipophilic conjugation, and nucleotide modifications.
Coronavirus genome expression inhibiting dsRNA agent
A dsRNA agent, or a salt thereof, comprises a sense strand and an antisense strand forming a double stranded region for inhibiting expression of a coronavirus genome in a cell.
Antisense strand sequence constrained by three-base difference
The antisense strand comprises a nucleotide sequence differing by no more than three bases from any one of the antisense strand nucleotide sequences selected from SEQ ID NO:586, SEQ ID NO:719, and SEQ ID NO:1852.
5′ phosphate or phosphate mimic on the antisense strand end
The dsRNA agent, or a salt thereof, further includes a phosphate or phosphate mimic at the 5′-end of the antisense strand.
5′-vinyl phosphonate phosphate mimic
A phosphate mimic is specifically a 5′-vinyl phosphonate (VP).
Lipophilic moieties including a C16 hydrocarbon chain
The dsRNA agent includes one or more lipophilic moieties comprising a saturated or unsaturated C16 hydrocarbon chain.
Nucleotide modifications across both strands
All nucleotides in both the sense strand and the antisense strand include a nucleotide modification.
Across the claims, the core inventive coverage is coronavirus-inhibitory dsRNA defined by a sense/antisense duplex with an antisense sequence restricted to within three bases of specified reference antisense sequences. Additional coverage includes antisense 5′-end phosphate or phosphate-mimic features, 5′-vinyl phosphonate, C16 lipophilic moieties, and nucleotide modifications across both strands.
Stated Advantages
Reduces off-target gene silencing by thermally destabilizing modifications in the antisense seed region (positions 2–9).
Enhanced in vivo activity via conjugation of one or more lipophilic moieties.
Inhibits expression of a coronavirus genome in a cell.
Inhibition of coronavirus genome expression and replication through RNA interference involving RISC.
Trivalent GalNAc conjugates are useful for RNAi gene-expression inhibition.
Documented Applications
Inhibiting expression of a coronavirus genome in a cell using RNAi agents or compositions, assessed by genome or protein measurements.
In vitro cell-based evaluation for inhibiting coronavirus genome-related readouts, including message reduction and replication-related measurements.
Use in cell-based assays measuring coronavirus-related outcomes, including nucleocapsid protein, ORF1ab, and ORF3AE readouts, including resistance-mutant evaluation contexts.
Use of coronavirus targets including SARS-CoV-2, SARS-CoV, and MERS-CoV in the document’s example context.
Therapeutic and prophylactic use for inhibiting expression of a coronavirus genome and treating coronavirus-associated diseases including SARS-CoV-2 (COVID-19), SARS-CoV, and MERS-CoV.
Pulmonary system administration including intranasal administration and inhalation for treating or preventing coronavirus-associated disease.
RNAi gene-expression inhibition, including inhibition of a coronavirus target gene.
RNAi delivery context including coronavirus RNAi delivery.
Delivery/formulation context for RNAi using pharmaceutical carriers such as liposomes and general nucleic-acid delivery vehicles.
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