Nuclease resistant external guide sequences for treating inflammatory and viral related respiratory diseases

Abstract

External Guide Sequence (EGS) are described that target proteins required for generation and modification of the immunoglobulin and T-cell repertoire that are useful for treatment or prevention of inflammatory or related diseases. Formulations suitable for administration of an EGS for treatment of inflammatory or related disease are described. The formulations may be administered via inhalation, injection, or orally. The formulations may be in the form of an ointment, lotion, cream, gel, drop, suppository, spray, liquid, powder, granule, solution, suspension, capsule, or tablet. Methods of treating inflammatory or related diseases by administering an effective amount of an EGS in a pharmaceutically acceptable carrier are also described. In preferred embodiments, the disease is asthma, allergic rhinitis, food allergies, atopic skin disease such as eczema, IL-4 and/or IL-13 dependent malignancies, IL-4 and/or IL-13 dependent autoimmune diseases, atopic diseases, the flu, and diseases caused by IL-4 dependent replication of viruses.

1 . A composition comprising a nuclease resistant external guide sequence (EGS) comprising the nucleotide sequence of SEQ ID NO: 14 and a pharmaceutically acceptable carrier, wherein the EGS binds to a cleavage site on a target RNA and the EGS guides RNase P to cleave the target RNA, thereby degrading the target RNA, wherein the target RNA encodes STAT6. 
     
     
         2 . The composition of  claim 1 , wherein the EGS has a chemical modification added to the 3′ end of the nucleotide sequence, wherein the chemical modification decreases susceptibility of the nucleotide sequence from exonuclease degradation. 
     
     
         3 . The composition of  claim 1 , wherein the EGS is formulated for administration via inhalation. 
     
     
         4 . A composition comprising the nuclease resistant EGS of  claim 1  in a dosage form for pulmonary administration. 
     
     
         5 . A method of treating an inflammatory disease, comprising administering an effective amount of a composition comprising a nuclease resistant EGS comprising the nucleotide sequence of SEQ ID NO: 14 and a pharmaceutically acceptable carrier, wherein the EGS binds to a cleavage site on a target RNA and the EGS guides RNaseP to cleave and degrade the target RNA, wherein the target RNA encodes STAT6. 
     
     
         6 . The method of  claim 5 , wherein the EGS inhibits expression of the target mRNA EGS and the composition inhibits or reduces one or more symptoms of the inflammatory disease.