Antisense compositions and methods for modulating contact hypersensitivity or contact dermatitis
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.
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.
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.
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:
where Y 1 ═O, Z═O, Pj is a purine or pyrimidine base-pairing moiety effective to bind, by base-specific hydrogen bonding, to a base in a polynucleotide, and X is alkyl, alkoxy, thioalkoxy, or alkyl amino e.g., wherein X═NR 2 , where each R is independently hydrogen or methyl.
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.
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:
where Y 1 ═O, Z═O, Pj is a purine or pyrimidine base-pairing moiety effective to bind, by base-specific hydrogen bonding, to a base in a polynucleotide, and X is alkyl, alkoxy, thioalkoxy, or alkyl amino e.g., wherein X═NR 2 , where each R is independently hydrogen or methyl.
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.