Treatment of atopic dermatitis and asthma using RNA complexes that target IL4Rα, TRPA1, or F2RL1
Inventors
Lee, Dong-Ki • Hong, Sun Woo • Lee, Hanna • Yu, Dayeon • Eom, Ji
Assignees
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Publication Number
US-10947541-B2
Publication Date
2021-03-16
Expiration Date
Abstract
In certain aspects, provided herein are RNA complexes (e.g., asymmetric RNA complexes, such as asiRNAs or cell penetrating asiRNAs) that inhibit IL4Rα, TRPA1, and/or F2RL1 expression and are therefore useful for treating atopic dermatitis or asthma.
Core Innovation
The document describes RNA-interference therapeutics for atopic dermatitis and asthma that inhibit expression of IL4Rα, TRPA1, and/or F2RL1 by administering asymmetric RNA complexes. The asymmetric RNA complexes include an antisense strand and a sense strand to induce RNA interference and thereby inhibit gene/protein expression associated with disease mechanisms.
Asymmetric RNA (asiRNA) is defined in the document in terms of strand length and antisense/sense complementarity, where the antisense strand is 19–21 nucleotides and the sense strand is 13–17 nucleotides. The document further emphasizes chemical modifications for delivery and activity, including 2′-O-methylation, phosphorothioate bonds, and hydrophobic moieties such as cholesterol.
The document reports screening and evaluation of multiple gene-targeting asiRNAs and cell-penetrating cp-asiRNAs, including sets directed to IL4Rα, TRPA1, and F2RL1. Candidate asiRNAs are tested for mRNA and protein knockdown, followed by evaluation of modified cp-constructs, with in vivo efficacy reported in an induced atopic dermatitis mouse model.
Claims Coverage
The provided claim set includes at least one independent claim focused on a nucleic acid complex for inducing RNA interference to inhibit F2RL1 gene expression. The inventive coverage is refined by dependent claims specifying strand definitions, duplex end structure, chemical modifications, and pharmaceutical formulation context.
RNA interference nucleic acid complex with antisense and sense strands
A nucleic acid complex comprising an antisense strand and a sense strand, where the nucleic acid complex induces RNA interference to inhibit expression of the F2RL1 gene.
Sequence-defined antisense strand for F2RL1 inhibition
The antisense strand is 21 nucleotides in length and has the base sequence of SEQ ID NO: 421.
Complementary sense strand for asymmetric RNA interference
The sense strand is 15 to 17 nucleotides in length and has sequence complementarity to the antisense strand.
Blunt ends at strand termini
The 5′ end of the antisense strand and the 3′ end of the sense strand form a blunt end.
Enumerated chemical modifications for the nucleic acid complex
The nucleic acid complex has a chemical modification selected from a 2′-O-methylated nucleoside, a phosphorothioate bond, or a hydrophobic moiety.
Pharmaceutical composition formulated for inhalation
A pharmaceutical composition formulated for inhalation.
Overall, the claim coverage centers on an asymmetric RNA interference nucleic acid complex for inhibiting F2RL1 gene expression, defined by a specific antisense sequence, a complementary sense strand, blunt-ended duplex termini, and enumerated chemical modification classes, with further coverage extending to pharmaceutical formulation for inhalation.
Stated Advantages
In vivo reduced scratching time in an induced atopic dermatitis mouse model compared to vehicle for IL4Rα/TRPA1/F2RL1-targeting cp-asiRNAs.
In vivo reduction in transepidermal water loss (TEWL) compared to vehicle for IL4Rα/TRPA1/F2RL1-targeting cp-asiRNAs.
Improved histology metrics compared to vehicle for IL4Rα/TRPA1/F2RL1-targeting cp-asiRNAs.
Reduced mast cell infiltration compared to vehicle for IL4Rα/TRPA1/F2RL1-targeting cp-asiRNAs.
Documented Applications
Therapeutic use in atopic dermatitis, including an induced atopic dermatitis mouse model with topical cream and intradermal injection contexts described in the document.
Therapeutic use in asthma, as stated in the document description of the RNA-interference therapeutics.
Inhibition of IL4Rα, TRPA1, and/or F2RL1 gene/protein expression using asymmetric RNA complexes (asiRNAs and cell-penetrating cp-asiRNAs).
Inhalation formulation of a pharmaceutical composition, as specified by a dependent claim member.
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