Antisense compositions and methods for modulating contact hypersensitivity or contact dermatitis

• US 8,592,386 B2
• Filed: 12/17/2009
• Issued: 11/26/2013
• Est. Priority Date: 12/17/2008
• Status: Active Grant

• Current Assignee: Sarepta Therapeutics, Inc.
• Original Assignee: Sarepta Therapeutics, Inc.
• Inventors: Mourich, Dan V., Marshall, Nikki B., Iversen, Patrick L.
• Primary Examiner(s): Angell, Jon E
• Application Number:
  US12/641,159
• Publication Number:
  US 20100184670A1
• Time in Patent Office: 1,440 Days
• Field of Search: 514/44.A, 536/24.5
• US Class Current: 514/44.A
• CPC Class Codes: A61K 31/7125 Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
• CPC Class Codes: A61K 38/19 Cytokines; Lymphokines; Interferons
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: C12N 15/1135 against oncogenes or tumor suppressor genes
• CPC Class Codes: C12N 15/1136 against growth factors, growth regulators, cytokines, lymphokines or hormones
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/3513 Protein; Peptide
• CPC Class Codes: C12N 2320/32 Special delivery means, e.g. tissue-specific

Abstract

Provided are methods and compositions, including topical compositions, for inducing tolerance to a sensitizing agent known to provoke contact hypersensitivity in a subject. Included are methods of topically applying to the subject an effective amount of an antisense composition targeting the start site or splice site of a CFLAR mRNA.

Claims

1. A method of reducing contact hypersensitivity or contact dermatitis, comprising contacting the skin or mucous membrane of a subject with a sensitizing agent and an effective amount of an antisense composition containing an antisense oligonucleotide,

wherein the sensitizing agent is a hapten or a metal ion complexed with a protein,

wherein the oligonucleotide contains between 12-40 nucleotide bases, and a base sequence effective to hybridize to at least 12 contiguous bases of a target sequence contained within SEQ ID NO:

11, wherein the oligonucleotide binding to the target sequence is effective to reduce expression of a functional human CFLAR in CFLAR-expressing lymphocytes, and thereby reducing contact hypersensitivity or contact dermatitis in the subject.

3. The method of claim 1, wherein the oligonucleotide is a peptide nucleic acid (PNA), a locked nucleic acid (LNA), an RNA interference agent with a duplex region, or a morpholino oligonucleotide.

4. The method of claim 3, wherein the morpholino oligonucleotide contains morpholino subunits that are joined by phosphorodiamidate linkages, in accordance with the structure:

5. The method of claim 3, wherein the intersubunit linkages are interspersed with linkages that are positively charged at physiological pH, where the total number of positively charged linkages is between 2 and no more than half of the total number of linkages.

6. The method of claim 5, wherein the positively charged linkages have a phosphorodiamidate structure in which X is 1-piperazine.

7. The method of claim 1, wherein the composition comprises a carrier or delivery vehicle for contacting the skin or mucous membrane.

8. The method of claim 7, wherein the carrier or delivery vehicle includes propylene glycol, an acyl-chain lipid, or both.

2. A method of reducing contact hypersensitivity or contact dermatitis, comprising contacting the skin or mucous membrane of a subject with a sensitizing agent and an effective amount of an antisense composition containing an antisense oligonucleotide,

wherein the sensitizing agent is an acid, an alkali, a solvent, a heavy metal, a rubber, latex, a surfactant, kerosene, chlorine, ethylene oxide, a cosmetic, an antiseptic, an insecticide, potassium dichromate, paraphenylenediamine, a dental product, formaldehyde, a fragrance, urushiol oil, an antibiotic, a topical steroid, a fungicide, or quaternium-15,

wherein the oligonucleotide contains between 12-40 nucleotide bases, and a base sequence effective to hybridize to at least 12 contiguous bases of a target sequence contained within SEQ ID NO:

11,

wherein the oligonucleotide binding to the target sequence is effective to reduce expression of a functional human CFLAR in CFLAR-expressing lymphocytes, and thereby reducing contact hypersensitivity or contact dermatitis in the subject.

9. The method of claim 2, wherein the oligonucleotide is a peptide nucleic acid (PNA), a locked nucleic acid (LNA), an RNA interference agent with a duplex region, or a morpholino oligonucleotide.

10. The method of claim 9, wherein the morpholino oligonucleotide contains morpholino subunits that are joined by phosphorodiamidate linkages, in accordance with the structure:

11. The method of claim 9, wherein the intersubunit linkages are interspersed with linkages that are positively charged at physiological pH, where the total number of positively charged linkages is between 2 and no more than half of the total number of linkages.

12. The method of claim 11, wherein the positively charged linkages have a phosphorodiamidate structure in which X is 1-piperazine.

13. The method of claim 2, wherein the composition comprises a carrier or delivery vehicle for contacting the skin or mucous membrane.

14. The method of claim 13, wherein the carrier or delivery vehicle includes propylene glycol, an acyl-chain lipid, or both.