Therapeutic targets for facioscapulohumeral muscular dystrophy

Abstract

The disclosure relates to methods and compositions for regulating expression of DUX4. In some aspects, methods described by the disclosure are useful for treating a disease associated with aberrant DUX4 expression (e.g., facioscapulohumeral muscular dystrophy).

1 .- 86 . (canceled) 
     
     
         87 . A method for treating a subject having facioscapulohumeral muscular dystrophy, the method comprising administering to the subject an indirect small molecule inhibitor of DUX4 gene expression, wherein the indirect small molecule inhibitor reduces DUX4 gene expression in the muscle cells of the subject. 
     
     
         88 . The method of  claim 87 , wherein the indirect small molecule inhibitor of DUX4 gene expression does not inhibit one or more myogenic regulatory genes. 
     
     
         89 . The method of  claim 88 , wherein the one or more myogenic regulatory gene is myogenin (MyoG), myoD, and myosin heavy chain (MyHC). 
     
     
         90 . The method of  claim 87 , wherein the muscle cell is a terminally differentiated muscle cell. 
     
     
         91 . The method of  claim 87 , wherein the subject is identified having FSHD based upon the presence of a transcriptionally active DUX4 gene. 
     
     
         92 . The method of  claim 87 , wherein the muscle cell comprises a dysregulated D4Z4 array at chromosome 4q35 prior to the administration of the indirect small molecule inhibitor of DUX4 gene expression. 
     
     
         93 . The method of  claim 92 , wherein the dysregulated D4Z4 array comprises fewer than 11 repeat units. 
     
     
         94 . The method of  claim 87 , further comprising assessing the DUX4 expression level of the subject before and/or after the administering, wherein a change in the DUX4 expression level indicates effectiveness of treating FSHD. 
     
     
         95 . The method of  claim 87 , wherein the indirect small molecule inhibitor of DUX4 gene expression is a kinase inhibitor. 
     
     
         96 . The method of  claim 95 , wherein the kinase is a serine-threonine kinase. 
     
     
         97 . The method of  claim 96 , wherein the subject is a human. 
     
     
         98 . The method of  claim 87 , wherein the indirect small molecule inhibitor of DUX4 gene expression is administered to the subject orally. 
     
     
         99 . A method for reducing DUX4 gene expression in a mammalian cell, the method comprising contacting the mammalian cell with an indirect small molecule inhibitor of DUX4 gene expression, wherein the indirect small molecule inhibitor reduces DUX4 gene expression in the mammalian cell. 
     
     
         100 . The method of  claim 99 , wherein the mammalian cell is a muscle cell. 
     
     
         101 . The method of  claim 100 , wherein the muscle cell is a terminally differentiated muscle cell. 
     
     
         102 . The method of  claim 99 , wherein the mammalian cell is a human cell. 
     
     
         103 . The method of  claim 99 , wherein the indirect small molecule inhibitor of DUX4 gene expression does not inhibit one or more myogenic regulatory genes in the cell. 
     
     
         104 . The method of  claim 103 , wherein the one or more myogenic regulatory gene is myogenin (MyoG), myoD, and myosin heavy chain (MyHC). 
     
     
         105 . The method of  claim 99 , wherein the cell comprises a transcriptionally active DUX4 gene. 
     
     
         106 . The method of  claim 99 , wherein the cell comprises a dysregulated D4Z4 array at chromosome 4q35 prior to the delivery of the indirect small molecule inhibitor of DUX4 gene expression. 
     
     
         107 . The method of  claim 106 , wherein the dysregulated D4Z4 array comprises fewer than 11 repeat units. 
     
     
         108 . The method of  claim 99 , wherein the indirect small molecule inhibitor of DUX4 gene expression is a kinase inhibitor. 
     
     
         109 . The method of  claim 108 , wherein the kinase is a serine-threonine kinase.