Antisense compositions and methods for modulating contact hypersensitivity or contact dermatitis

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.

1 . A method of inducing tolerance to a sensitizing agent, comprising
 topically applying to a subject, an effective amount of an antisense composition containing an antisense oligonucleotide, wherein the oligonucleotide contains morpholino subunits and phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ exocyclic carbon of an adjacent subunit, 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.   
     
     
         2 . The method of  claim 1 , wherein the antisense oligonucleotide comprises a cell-penetrating peptide capable of enhancing uptake of the oligonucleotide into activated T cells. 
     
     
         3 . The method of  claim 1 , comprising continuing said applying step on a periodic basis to reduce skin or mucous membrane inflammation resulting from contact with the agent. 
     
     
         4 . The method of  claim 1 , wherein the composition is applied to a skin area of the subject prior to contact or after contact with the sensitizing agent. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the sensitizing agent is i) skin or mucous membrane irritant selected from the group consisting of an acid, an alkali, a solvent, a heavy metal, rubber, latex, a cosmetic, and a fragrance, or ii) a skin allergen from a plant containing urushiol oil. 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 6 , wherein the plant is selected from the group consisting poison oak, poison ivy, and poison sumac. 
     
     
         9 . The method of  claim 1 , wherein the composition comprises a carrier or delivery vehicle for topical administration. 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 1 , wherein the oligonucleotide in the conjugate has a base sequence effective to hybridize to at least 12 contiguous bases of a target sequence contained within SEQ ID NO:12. 
     
     
         12 . The method of  claim 2 , wherein the cell-penetrating peptide is an arginine-rich peptide. 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 1 , wherein the morpholino subunits in the oligonucleotide are joined by phosphorodiamidate linkages, in accordance with the structure: 
       
         
           
           
               
               
           
         
         where Y 1 ═, 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. 
       
     
     
         15 . The method of  claim 14 , wherein the intersubunit linkages, which are uncharged, 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. 
     
     
         16 . The method of  claim 15 , wherein the positively charged linkages have a phosphorodiamidate structure in which X is 1-piperazine. 
     
     
         17 . A composition adapted for topical administration, comprising
 an antisense oligonucleotide, wherein the oligonucleotide contains morpholino subunits and phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ exocyclic carbon of an adjacent subunit, 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, and   a delivery vehicle or carrier for topical uptake of the composition.   
     
     
         18 . The composition of  claim 17 , wherein the antisense oligonucleotide comprises a cell-penetrating peptide capable of enhancing uptake of the oligonucleotide into activated T cells. 
     
     
         19 . (canceled) 
     
     
         20 . The composition of  claim 17 , wherein the oligonucleotide has a base sequence effective to hybridize to at least 12 contiguous bases of a target sequence contained within SEQ ID NO:12. 
     
     
         21 . The composition of  claim 18 , wherein the cell-penetrating peptide is an arginine-rich peptide. 
     
     
         22 . (canceled) 
     
     
         23 . The composition  claim 17 , wherein the morpholino subunits in the oligonucleotide are joined by phosphorodiamidate linkages, in accordance with the structure: 
       
         
           
           
               
               
           
         
         where Y 1 ═, 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. 
       
     
     
         24 . The composition of  claim 23 , wherein the intersubunit linkages, which are uncharged, 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. 
     
     
         25 . The composition of  claim 24 , wherein the positively charged linkages have a phosphorodiamidate structure in which X is 1-piperazine. 
     
     
         26 . The composition of  claim 17 , further comprising a sensitizing agent. 
     
     
         27 - 36 . (canceled)