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Topical administration of at least one double-stranded RNA oligonucleotide (dsRNA)

a technology of rna oligonucleotide and double-stranded rna, which is applied in the field of topical administration of at least one double-stranded rna oligonucleotide (dsrna), can solve the problems of inability to achieve the quantity, application limitations, and inability to achieve desirable effects, and achieve the effect of reducing the quantity of double-stranded rna oligonucleo

Inactive Publication Date: 2005-10-06
LOREAL SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015] Topical administration according to the invention both possesses the features mentioned above and makes it possible to ameliorate or overcome the difficulties which have thus far been encountered.
[0017] The double-stranded RNA oligonucleotides make it possible to specifically inhibit a gene (or several genes in the case of a composition which combines double-stranded RNA oligonucleotides which possess different sequences and which are targeted at mRNAs encoding different proteins).
[0019] Too, because of their duplex structure, these double-stranded RNA oligonucleotides are unable to undergo folding and self-pairing; in this way, the bioavailability of the active product, that is to say the quantity of double-stranded RNA oligonucleotide which produces the desired effect and which arises in the cells, is markedly improved and makes it possible to use lower quantities of double-stranded RNA oligonucleotide.
[0020] The compositions comprising the double-stranded RNA according to the invention are particularly suitable for cosmetic or dermatological administration since they make it possible to reach the target cell without an invasive mode of administration and are active without having to penetrate into the cell nucleus.

Problems solved by technology

However, such application has its limitations.
Thus, including DNA, non-specific RNA or antisense DNA oligonucleotides (such as those described, for example, in WO 01 / 58918) in topical formulations has not enabled any desirable efficacy to be obtained.
In particular, RNases on the surface of the skin degrade native RNA and it is not possible for the quantities reaching the target mRNAs to be sufficient to obtain the desired effect.
Another limitation to administering single-stranded oligonucleotides such as those mentioned above is the risk of the oligonucleotide possibly undergoing secondary refolding (or secondary re-pairing).
For this reason, administering single-stranded oligonucleotides (such as antisense DNA oligonucleotides) in vivo is frequently ineffective.
Furthermore, the stability of the effects produced by single-stranded oligonucleotides in vivo is short because of the oligonucleotides being broken down rapidly intracellularly and having a short extracellular half-life in vivo (Khan A et al., J.

Method used

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  • Topical administration of at least one double-stranded RNA oligonucleotide (dsRNA)
  • Topical administration of at least one double-stranded RNA oligonucleotide (dsRNA)
  • Topical administration of at least one double-stranded RNA oligonucleotide (dsRNA)

Examples

Experimental program
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Effect test

example 1

Using RNA Interference to Inhibit the Expression of Tyrosinase:

[0206] Materials and Methods:

[0207] The experimental conditions are those described by Tuschl et al. (Journal of Cell Science, 2001, 114, 45574565).

[0208] 24 h before transfection, the melanocytes (MeWo cells) are sown, at the rate of 40,000 cells / well, in 500 μl of DMEM medium+10% serum in a 24-well plate. 0.84 μg or 2.52 μg of duplex siRNA (see description below), that is 60 pmol of tyrosinase siRNA in 3 μl of annealing buffer (Dharmacon) or, respectively, 180 pmol of tyrosinase siRNA in 9 μl of annealing buffer, are used per well. 3 μl or 9 μl of 20 μM tyrosinase duplex siRNA are diluted in 50 μl of Opti-MEM (Gibco). In another tube, 3 μl of oligofectamine (Invitrogen) are diluted in 12 μl of Opti-MEM and incubated at room temperature for 10 minutes. The 2 solutions are mixed and incubated at room temperature for 20 minutes before being added to the cells. The cells are then incubated at 37° C. for 96 h, with a cha...

example 2

Compositions:

[0229] Composition 1: The double-stranded RNA oligonucleotide is complexed on the surface of cationic vesicles:

[0230] Preparing the vesicles:

PEG 400 isostearate8%Polyethyleneimine (PEI of 200 to 100 000 MW)2%amidified with isostearic acidDistilled waterqs for 100%

[0231] Double-stranded RNA oligonucleotides of SEQ ID No. 1 and SEQ ID No. 2, with a dsRNA / PEI ratio of between 0.1 and 1000.

[0232] Steps Involved in Preparing Vesicles: [0233] solubilizing the lipids in a methanol / chloroform mixture; [0234] evaporating the solvent in a rotary evaporator under reduced pressure in order to obtain a lipid film; [0235] hydrating the film while ultrasonicating; [0236] checking the diameter of the vesicles (less than 1 μm; preferably 200 nm); [0237] adding the solution of double-stranded RNA oligonucleotides.

[0238] Cosmetic Composition:

[0239] The vesicles are then incorporated into a cosmetic formulation which is suitable for topical application.

[0240] Daily application, pre...

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Abstract

Expression of a messenger RNA which encodes a protein which is expressed by differentiated cells, notably the cells of the skin or appendages thereof, is inhibited by topically administering to said differentiated cells a thus effective amount of at least one double-stranded RNA oligonucleotide, formulated into a topically applicable, physiologically acceptable medium therefor; such regime or regimen is useful for treating a variety of afflictions or conditions, e.g., combating the signs of skin aging, stimulating hair growth or retarding loss thereof, inhibiting cellular proliferation and / or differentiation, etc.

Description

CROSS-REFERENCE TO PRIORITY / PCT / PROVISIONAL APPLICATIONS [0001] This application claims priority under 35 U.S.C. § 119 of FR-02 / 06796, filed Jun. 3, 2002, and of provisional application Ser. No. 60 / 386,720, filed Jun. 10, 2002, and is a continuation of PCT / FR 2003 / 001648, filed Jun. 2, 2003 and designating the United States (published in the French language on Dec. 11, 2003, as WO 2003 / 101376 A3; the title and abstract were also published in English), each hereby expressly incorporated by reference and each assigned to the assignee hereof.BACKGROUND OF THE INVENTION [0002] 1. Technical Field of the Invention [0003] The present invention relates to the administration of at least one double-stranded RNA oligonucleotide (dsRNA) via topical application and to compositions for topical administration which comprise at least one encapsulated double-stranded RNA oligonucleotide formulated into a physiologically acceptable medium therefor. [0004] 2. Description of Background and / or Related a...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K8/60A61K31/7088A61Q7/00A61Q17/02A61Q19/00A61Q19/02A61Q19/08
CPCA61K8/606A61K31/7088A61Q7/00A61Q19/00A61Q19/007A61Q19/02A61Q19/08C12N2310/13
Inventor DURANTON, ALBERTCOLLIN-DJANGONE, CHRISTINEPRUCHE, FRANCISSIMONNET, JEAN-THIERRY
Owner LOREAL SA
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