RNA complexes that inhibit melanin production
Inventors
Hong, Sun Woo • Hong, Isu • Kim, Ji Hyun
Assignees
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Publication Number
US-10512600-B2
Publication Date
2019-12-24
Expiration Date
Abstract
In certain aspects, provided herein are RNA complexes (e.g., asymmetric RNA complexes, such as asiRNAs and lasiRNAs) that inhibit tyrosinase expression and are therefore useful for reducing melanin production and for treating pigmentation-related disorders associated with excessive melanin production, such as melasma and age spots.
Core Innovation
The invention relates to asymmetric RNA (asiRNA) complexes, including long asymmetric siRNA (lasiRNA), for inhibiting tyrosinase expression and reducing melanin production in a subject. The specification describes using cell-penetrating asiRNAs (cp-asiRNAs) designed to inhibit tyrosinase mRNA/protein expression and melanin accumulation. The document emphasizes treating pigmentation disorders such as melasma and age spots by targeting tyrosinase expression.
The core asiRNA is an asymmetric RNA complex comprising an antisense strand and a sense strand that form a complex in which the 5′ end of the antisense strand and the 3′ end of the sense strand form a blunt end. The antisense strand has sequence complementarity to a tyrosinase mRNA sequence, and the sense strand has sequence complementarity to the antisense strand. A cholesterol moiety is attached to the 3′ end of the sense strand.
The document further describes chemically modified cell-penetrating asiRNAs intended for uptake without a transfection vehicle. It includes modifications such as 2′-O-methyl nucleosides and phosphorothioate bonds, and it describes cholesterol moiety attachment. The specification also describes topical pharmaceutical compositions for contacting or administering the RNA to skin and reports reduced melanin content, inhibition of tyrosinase expression, and low cytotoxicity relative to hydroquinone or arbutin.
Claims Coverage
The independent claim contains multiple inventive limitations that define a topical, transfection-reagent-free method using a specific blunt-end cp-asiRNA architecture that targets tyrosinase mRNA. The dependent claims refine the asiRNA chemistry and structure, and they narrow the therapeutic context to skin pigmentation disorders associated with excessive melanin production, including melasma and age spots. Across the claim set, the inventive features are centered on tyrosinase mRNA targeting, the blunt-end asiRNA complex geometry, transfection-reagent absence, and 3′ cholesterol moiety presentation, with further refinements to nucleic-acid chemistry and treatment indications.
Topical transfection-reagent-free inhibition of tyrosinase expression with blunt-end cp-asiRNA
Administering topically, in the absence of a transfection reagent, to the skin of a subject a cell-penetrating asymmetric RNA (asiRNA) comprising an antisense strand of 19 to 21 nucleotides complementary to a tyrosinase mRNA sequence and a sense strand of 15 to 17 nucleotides complementary to the antisense strand, wherein the antisense and sense strands form a complex with the 5′ end of the antisense strand and the 3′ end of the sense strand forming a blunt end.
Cholesterol moiety on the sense strand terminus for the asiRNA complex
Providing the sense strand with a cholesterol moiety attached to the 3′ end thereof in the cell-penetrating asiRNA complex administered to the skin.
Phosphorothioate-modified asiRNA
Including at least one phosphorothioate bond in the asiRNA.
Four phosphorothioate bonds at the 3′ end of the antisense strand
Forming four phosphorothioate bonds at the 3′ end of the antisense strand.
Effective amount for treating skin pigmentation disorders associated with excessive melanin production
Administering the asiRNA in an effective amount to treat a skin pigmentation disorder associated with excessive melanin production.
Treatment of melasma or age spots
Treating a skin pigmentation disorder that includes melasma or age spots.
Topical cream or lotion formulation for delivering the asiRNA
Formulating the asiRNA as part of a cream or lotion.
Overall, the claims cover a topical method for inhibiting tyrosinase expression using a cell-penetrating asiRNA complex that is applied without a transfection reagent, with an antisense/sense blunt-end architecture and a cholesterol moiety attached to the sense strand 3′ end. Dependent claim refinements further constrain phosphorothioate chemistry and narrow use to skin pigmentation disorders characterized by excessive melanin production, including melasma and age spots, with delivery via cream or lotion.
Stated Advantages
Inhibits tyrosinase expression.
Reduces melanin production.
Supports topical delivery to skin without a transfection vehicle.
Shows reduced cytotoxicity relative to hydroquinone or arbutin.
Demonstrates activity in reconstructed 3-D skin models.
Documented Applications
Treating pigmentation disorders such as melasma and age spots by inhibiting tyrosinase expression and reducing melanin production in a subject.
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