Methods for treating aging and skin disorders using nucleic acids targeting TYR or MMP1
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Publication Number
US-11926828-B2
Publication Date
2024-03-12
Expiration Date
Abstract
The present invention relates to RNAi constructs with improved tissue and cellular uptake characteristics and methods of use of these compounds in dermal applications.
Core Innovation
Embodiments describe chemically modified double stranded nucleic acid molecules comprising an antisense strand and a sense strand, where the region of the molecule that is double stranded is from 8-15 nucleotides long and the antisense strand contains a single stranded region from 4-12 nucleotides long. The single stranded region contains phosphorothioate modifications, and at least 40% of the nucleotides of the double stranded nucleic acid molecule are modified.
The sense strand comprises SEQ ID NO: 24 or at least 12 contiguous nucleotides of sequences selected from SEQ ID NOs 3, 8-9, 37-38 and 186, and the antisense strand comprises SEQ ID NO: 65 or at least 12 contiguous nucleotides of sequences selected from SEQ ID NOs 44, 49-50, 78-79 and 215. The constructs are presented with modified nucleic acid and linkage patterns, including phosphorothioate and other phosphodiester analogs, and with variable substituents including R1, R2 and R3.
The disclosed molecules include hydrophobic conjugates such as cholesterol, where R1 is a hydrophobic moiety, R2 can be hydrogen or an oxygen-protecting group, and R3 is a nucleic acid. The molecular designs include regions described as RNase H activating versus non-activating within antisense/chimeric oligonucleotides, and include concepts for RISC loading.
The embodiments further describe self-delivering reduced-size RNAi (sd-rxRNA) targeting TYR (tyrosinase) and MMP1, including reducing melanin pigmentation. The disclosed uses include treating multiple conditions involving melanocytes/pigmentation, including Addison’s disease, Parkinson’s disease, and keloids, and treating neoplasms by targeting proliferative genes using sd-rxRNA.
Claims Coverage
The independent claim coverage centers on a chemically modified double stranded nucleic acid molecule with defined strand lengths, modification patterning, and sequence requirements based on specified SEQ ID NOs. The claim coverage centers on four inventive features, with dependent claims adding structural, conjugate, formulation, and therapeutic limitations.
Defined double-stranded nucleic acid architecture
A chemically modified double stranded nucleic acid molecule comprising an antisense strand and a sense strand, where the region of the molecule that is double stranded is from 8-15 nucleotides long and the antisense strand contains a single stranded region that is 4-12 nucleotides long.
Phosphorothioate modification patterning
The single stranded region of the antisense strand contains 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 phosphorothioate modifications, and at least 40% of the nucleotides of the double stranded nucleic acid molecule are modified.
Sense and antisense sequence requirements from SEQ ID NOs
The sense strand comprises the sequence of SEQ ID NO: 24 or comprises at least 12 contiguous nucleotides of a sequence selected from SEQ ID NOs 3, 8-9, 37-38 and 186, and the antisense strand comprises the sequence of SEQ ID NO: 65 or comprises at least 12 contiguous nucleotides of a sequence selected from SEQ ID NOs 44, 49-50, 78-79 and 215.
Hydrophobic conjugate attachment
A hydrophobic conjugate is attached to the chemically modified double stranded nucleic acid molecule.
Across the independent and dependent claims in the provided material, the claims coverage centers on a chemically modified double stranded nucleic acid defined by strand-length architecture, antisense phosphorothioate modification within a defined single stranded region, and sequence requirements using specified SEQ ID NOs, with dependent claims further refining hydrophobic conjugate attachment and therapeutic use.
Stated Advantages
Improves serum stability.
Improves cellular uptake.
Improves potency.
Reduces toxicity.
Reduces off-target gene silencing.
Reduces interferon induction.
Reduces melanin pigmentation.
Increase stability.
Promote RISC loading.
Documented Applications
RNAi therapy for skin disorders and aging using self-delivering asymmetric double-stranded rxRNA/sd-rxRNA constructs targeting MMP1, TYR and PTGS2.
Therapeutic treatment of tuberculosis, arthritis, corneal erosions, periodontitis, endometrial cancer, or endometriosis by administering a therapeutically effective amount of the chemically modified double-stranded nucleic acid molecule.
Topical delivery and skin delivery using compositions containing the chemically modified double-stranded nucleic acid molecule.
Intradermal injection and extended release after intradermal injection using compositions containing the chemically modified double-stranded nucleic acid molecule.
Administration of two or more nucleic acid molecules to a subject, where the nucleic acids target genes encoding different proteins or genes encoding the same protein.
Treating multiple conditions involving melanocytes/pigmentation, including Addison’s disease, Parkinson’s disease, and keloids.
Treating neoplasms by targeting proliferative genes, including epithelial origin neoplasms, mesenchymal/sarcoma, and melanocytic cancers.
Treating tuberculosis.
Treating arthritis (osteo and rheumatoid).
Treating corneal erosions.
Treating periodontitis.
Treating endometrial cancer.
Treating endometriosis.
Topical delivery, skin delivery, intradermal injection, and extended release after intradermal injection formulations.
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