Compositions and Methods for Identifying and Treating Dystonia Disorders

Abstract

The present disclosure provides methods and compositions for the treatment, identification, diagnosis, and prognosis of dystonia, or dystonia related disorders.

1 .- 27 . (canceled) 
     
     
         28 . A method of predicting a subject's risk of developing a dystonia, the method comprising:
 obtaining a biological sample from a subject;   measuring the expression level of one or more biomarkers in the biological sample;   comparing the expression level of the one or more biomarkers in the biological sample to a control expression level for the one or more biomarkers,
 wherein the subject is at risk of developing a dystonia when the expression level of the one or more biomarkers in the subject's biological sample is greater than the control expression level of the one or more biomarkers. 
   
     
     
         29 . The method of  claim 28 , wherein the one or more biomarkers comprise components of the eIF2-alpha signaling pathway. 
     
     
         30 . The method of  claim 28 , wherein the one or more biomarkers comprise Torsin1a, ATF4, BiP, eIF2-alpha, GADD34, CReP, HERPUD1, RAP1A, and MAP2K5, variants and mutations thereof, or any combination thereof. 
     
     
         31 . The method of  claim 28 , wherein the one or more biomarkers comprise one or more mutations in the wild-type ATF4 protein. 
     
     
         32 . The method of  claim 31 , wherein the one or more mutations in the wild-type ATF4 protein comprise
 a mutation at position 35 of the wild-type ATF4 protein sequence;   a mutation at position 37 of the wild-type ATF4 protein sequence;   a mutation at position 46 of the wild-type ATF4 protein sequence; or   a mutation at position 296 of the wild-type ATF4 protein sequence.   
     
     
         33 . The method of  claim 32 , wherein the mutation at position 35 comprises an aspartic acid to tyrosine substitution; wherein the mutation at position 37 comprises a tyrosine to phenylalanine substitution; wherein the mutation at position 46 comprises a proline to leucine substitution; or wherein the mutation at position 296 comprises an arginine to lysine substitution. 
     
     
         34 . The method of  claim 28 , wherein measuring the expression level of the one or more biomarkers comprises using an antibody, a nucleic acid, a receptor, a binding partner, or an aptamer with specific affinity for the one or more biomarkers. 
     
     
         35 . The method of  claim 28 , wherein the subject is a human. 
     
     
         36 . The method of  claim 28 , wherein the biological sample comprises tissues, cells, biopsies, blood, cerebrospinal fluid, lymph, serum, plasma, urine, saliva, mucus, or tears. 
     
     
         37 . The method of  claim 28 , wherein the dystonia is inherited, familial, or sporadic. 
     
     
         38 . The method of  claim 28 , wherein the dystonia is DYT1 dystonia. 
     
     
         39 . The method of  claim 28 , further comprising administering to the subject an anti-dystonia therapy. 
     
     
         40 . The method of  claim 39 , wherein the anti-dystonia therapy comprises one or more agents capable of modulating the intracellular pathway controlled by eIF2-alpha, one or more agents capable of modulating the integrated stress response, or one or more agents capable of modulating the phosphorylation state of eIF2-alpha. 
     
     
         41 . The method of  claim 40 , wherein the one or more agents capable of modulating the phosphorylation state of eIF2-alpha comprise salubrinal, Sal-003, or guanabenz. 
     
     
         42 . The method of  claim 39 , wherein the anti-dystonia therapy comprises one or more agents capable of correcting TorsinA mis-localization. 
     
     
         43 . The method of  claim 42 , wherein the one or more agents capable of correcting TorsinA mis-localization comprise one or more HIV protease inhibitors. 
     
     
         44 . The method of  claim 43 , wherein the one or more HIV protease inhibitors comprise ritonavir, lopinavir, saquinavir, nelfinavir, or indinavir. 
     
     
         45 . The method of  claim 39 , further comprising administering to the subject an oral medication. 
     
     
         46 . The method of  claim 45 , wherein the oral medication comprises an anticholinergic, a benzodiazepine, a dopaminergic agent, a dopamine-depleting agent, baclofen, or tetrabenezine. 
     
     
         47 . The method of  claim 39 , further comprising monitoring the subject's response to the anti-dystonia therapy.