COMPOSITION FOR PREVENTION OR TREATMENT OF INTRACTABLE EPILEPSY COMPRISING mTOR INHIBITOR

Abstract

Provided is a use of the prophylaxis, amelioration or therapy of intractable epilepsy, for example, Focal Cortical Dysplasia (FCD).

1 . A method for preventing or treating an intractable epilepsy or a disease causing intractable epilepsy, comprising administering an effective amount of a mTOR inhibitor as an active ingredient. to a subject in need. 
     
     
         2 . The method of  claim 1 , wherein the intractable epilepsy is caused by Focal Cortical Dysplasia (FCD). 
     
     
         3 . The method of  claim 1 , wherein the intractable epilepsy is caused by cerebral somatic mutation-associated with FCD. 
     
     
         4 . The method of  claim 1 , wherein the mTOR inhibitor is selected from the group consisting of AMG954, AZD8055, AZD2014, BEZ235, BGT226, Everolimus, Sirolimus, CC-115, CC-223, LY3023414, P7170, DS-7423, OSI-027, GSK2126458, PF-04691502, PF-05212384, Temsirolimus, INK128, MLN0128, MLN1117, Ridaforolimus, Metformin, XL765, SAR245409, SF1126, VS5584, GDC0980 and GSK2126458, and a pharmaceutically-acceptable salts thereof. 
     
     
         5 . The method of  claim 1 , wherein the mTOR inhibitor is selected from the group consisting of Rapamycin or its salts, Everolimus and its salts, the compounds represented by chemical formulae 1 to 4 and their salts: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method of  claim 3 , wherein the cerebral somatic mutation comprises at least one selected from the group consisting of amino acid substitutions of from arginine (R) at position 206 to cysteine (C), from R at position 624 to H, from Y at position 1450 to D, from C at position 1483 to R, from R at position 1709 to H, from T at position 1977 to K, from R at position 2193 to C, from S at position 2215 to F, from L at position 2427 to P, and from L at position 2427 to Q in an amino acid of SEQ ID NO: 2,
 amino acid substitutions of from arginine (R) at position 22 to tryptophan (W), from R at position 204 to C, and from R at position 811 to L in an amino acid of SEQ ID NO: 4,   amino acid substitution of from valine (V) at position 1547 to isoleucine (I) in an amino acid of SEQ ID NO: 6,   amino acid substitution of from arginine (R) at position 247 to histidine (H) in an amino acid of SEQ ID NO: 8, and   amino acid substitution of from aspartic acid (D) at position 1018 to asparagine (N) in an amino acid of SEQ ID NO: 10.   
     
     
         7 . The method of  claim 1 , wherein the cerebral somatic mutation include at least one selected from the group consisting of nucleotide mutations of from Cytosine (C) at position 616 to Thymine (T), from Guanine (G) at position 1871 to Adenine (A), from Thymine (T) at position 4348 to Guanine (G), from Thymine (T) at position 4447 to Cytosine (C), from Guanine (G) at position 5126 to Adenine (A), from Cytosine (C) at position 5930 to Adenine (A), from Cytosine (C) at position 6577 to Thymine (T), from Cytosine (C) at position 6644 to Thymine (T), from Thymine (T) at position 7280 to Cytosine (C), from Thymine (T) at position 7280 to Adenine (A) in an amino acid of SEQ ID NO: 1,
 nucleotide mutations of from Cytosine (C) at position 64 to Thymine (T), from Cytosine (C) at position 610 to Thymine (T), and from Guanine (G) at position 2432 to Thymine (T) in an amino acid of SEQ ID NO: 3,   nucleotide mutation of from Guanine (G) at position 4639 to Adenine (A) in an amino acid of SEQ ID NO: 5,   nucleotide mutation of from Guanine (G) at position 740 to Adenine (A) in an amino acid of SEQ ID NO: 7, and   nucleotide mutation of from Guanine (G) at position 3052 to Adenine (A) in an amino acid of SEQ ID NO: 9.   
     
     
         8 . The method of  claim 1 , further comprising a compound selected from the group consisting of a pharmaceutically acceptable diluent, excipient, stabilizing agent, surfactant, gelling agent, pH adjusting agent, anti-oxidant and preservative. 
     
     
         9 . The method of  claim 3 , wherein the cerebral somatic mutation is an amino acid substitution or a nucleotide mutation encoding the amino acid in mTOR, TSC1, TSC2, AKT3, or PIK3CA protein or gene encoding the protein. 
     
     
         10 - 16 . (canceled) 
     
     
         17 . A method for diagnosing an intractable epilepsy or a disease causing intractable epilepsy, comprising:
 (a) treating a sample of a subject with a diagnostic kit comprising an agent detecting at least one amino acid substitution or an agent detecting at least one nucleotide mutation encoding the amino acid substitution;   (b) detecting in the sample a biomarker panel comprising at least one amino acid substitution or at least one nucleotide mutation encoding the amino acid substitution, wherein the at least one amino acid substitution,   wherein the amino acid substitutions is at least one selected from the group consisting of amino acid substitutions of from arginine (R) at position 206 to cysteine (C), from R at position 624 to H, from Y at position 1450 to D, from C at position 1483 to R, from R at position 1709 to H, from T at position 1977 to K, from R at position 2193 to C, from S at position 2215 to F, from L at position 2427 to P, and from L at position 2427 to Q in an amino acid of SEQ ID NO: 2, amino acid substitutions of from arginine (R) at position 22 to tryptophan (W), from R at position 204 to C, and from R at position 811 to L in an amino acid of SEQ ID NO: 4, amino acid substitution of from valine (V) at position 1547 to isoleucine (I) in an amino acid of SEQ ID NO: 6, amino acid substitution of from arginine (R) at position 247 to histidine (H) in an amino acid of SEQ ID NO: 8, and amino acid substitution of from aspartic acid (D) at position 1018 to asparagine (N) in an amino acid of SEQ ID NO: 10; and   (c) determining the onset of intractable epilepsy if the biomarker panel containing one or more of amino acid substitutions is detected.   
     
     
         18 . The method of  claim 17 , wherein the sample is brain tissue. 
     
     
         19 . The method of  claim 17 , wherein the amino acid substitution is selected from the group consisting of an amino acid substitution of from Cytosine (C) at position 616 to Thymine (T) in an amino acid of SEQ ID NO: 2,
 an amino acid substitution of from arginine (R) at position 22 to tryptophan (W) in an amino acid of SEQ ID NO: 4,   an amino acid substitution of from valine (V) at position 1547 to isoleucine (I) in an amino acid of SEQ ID NO: 6,   an amino acid substitution of from arginine (R) at position 247 to histidine (H) in an amino acid of SEQ ID NO: 8, and   an amino acid substitution of from aspartic acid (D) at position 1018 to asparagine (N) in an amino acid of SEQ ID NO: 10.   
     
     
         20 . The method of  claim 17 , wherein the nucleotide mutation is at least one selected from the group consisting of a nucleotide mutation of Cytosine (C) at position 616 to Thymine (T) in an amino acid of SEQ ID NO: 1,
 nucleotide mutation of from Cytosine (C) at position 64 to Thymine (T) in an amino acid of SEQ ID NO: 3,   nucleotide mutation of from Guanine (G) at position 4639 to Adenine (A) in an amino acid of SEQ ID NO: 5,   nucleotide mutation of from Guanine (G) at position 740 to Adenine (A) in an amino acid of SEQ ID NO: 7, and   nucleotide mutation of from Guanine (G) at position 3052 to Adenine (A) in an amino acid of SEQ ID NO: 9.   
     
     
         21 . The method of  claim 17 , wherein the agent detecting the nucleotide mutation is a primer, a probe or an antisense nucleic acid that is specific for a mutation region. 
     
     
         22 . The method of  claim 17 , wherein the agent detecting the amino acid substitution is an antibody or an aptamer that is specific for a substitution region. 
     
     
         23 . An animal with an intractable epilepsy or a disease causing intractable epilepsy which is induced by a protein or a polynucleotide,
 wherein the protein is selected from the group consisting of a protein comprising an amino acid substitution of from Cytosine (C) at position 616 to Thymine (T) in an amino acid of SEQ ID NO: 2, an amino acid substitution of from arginine (R) at position 22 to tryptophan (W) in an amino acid of SEQ ID NO: 4, an amino acid substitution of from valine (V) at position 1547 to isoleucine (I) in an amino acid of SEQ ID NO: 6, an amino acid substitution of from arginine (R) at position 247 to histidine (H) in an amino acid of SEQ ID NO: 8, and an amino acid substitution of from aspartic acid (D) at position 1018 to asparagine (N) in an amino acid of SEQ ID NO: 10, or   the polynucleotide that is selected from the group consisting of a polynucleotide comprising a nucleotide mutation of Cytosine (C) at position 616 to Thymine (T) in an amino acid of SEQ ID NO: 1, nucleotide mutation of from Cytosine (C) at position 64 to Thymine (T) in an amino acid of SEQ ID NO: 3, nucleotide mutation of from Guanine (G) at position 4639 to Adenine (A) in an amino acid of SEQ ID NO: 5, nucleotide mutation of from Guanine (G) at position 740 to Adenine (A) in an amino acid of SEQ ID NO: 7, and nucleotide mutation of from Guanine (G) at position 3052 to Adenine (A) in an amino acid of SEQ ID NO: 9.   
     
     
         24 . (canceled)