Compositions and Methods for Uncoupling TrkB Receptor from PLC Gamma 1 for the Treatment of Epilepsy and Anxiety-Like Disorder

Abstract

The invention provides pharmaceutical compositions and methods of use thereof for preventing or ameliorating disorders of the nervous system. More specifically, the invention provides pharmaceutical compositions, including phosphopeptides that when administered disrupt the physical interaction of TrkB with its signaling effector, phospholipase Cγ1 (PLCγ1). The invention further provides method of treatment comprising administering phosphopeptides that uncouple TrkB from PLCγ1 in order to prevent and/or ameliorate nervous system disorders such as epilepsy, anxiety, and seizures.

1 .- 16 . (canceled) 
     
     
         17 . A method of treating or ameliorating a disorder of the nervous system in a subject, the method comprising:
 administering to a subject a therapeutically effective amount of an interfering molecule,
 wherein the interfering molecule inhibits tyrosine receptor kinase B (TrkB)-mediated activation of phospholipase C gamma 1 (PLCγ1), and 
 wherein the interfering molecule comprises a phosphopeptide comprising the amino acid sequence set forth in SEQ ID NO: 3 or SEO ID NO: 5. 
   
     
     
         18 . The method of  claim 17 , wherein a disorder of the nervous system comprises stroke, anxiety, epilepsy, head trauma, migraine, pain, schizophrenia, affective disorders, addiction, and any combination thereof. 
     
     
         19 . The method of  claim 17 , wherein the subject is a human. 
     
     
         20 . The method of  claim 17 , wherein the interfering molecule is capable of permeating the blood brain barrier. 
     
     
         21 . The method of  claim 17 , wherein the interfering molecule inhibits the physical interaction of TrkB and PLCγ1. 
     
     
         22 . The method of  claim 17 , wherein the phosphopeptide comprises the amino acid sequence set forth in SEQ ID NO: 3. 
     
     
         23 . The method of  claim 17 , wherein the phosphopeptide comprises the amino acid sequence set forth in SEQ ID NO: 5. 
     
     
         24 . A method for preventing onset or limiting the progression of a disorder of the nervous system in a subject, the method comprising:
 administering to a subject a therapeutically effective amount of an interfering molecule,
 wherein the interfering molecule inhibits tyrosine receptor kinase B (TrkB)-mediated activation of phospholipase C gamma 1 (PLCγ1), and 
 wherein the interfering molecule comprises a phosphopeptide comprising the amino acid sequence set forth in SEQ ID NO: 3 or SEO ID NO: 5. 
   
     
     
         25 . The method of  claim 24 , wherein a disorder of the nervous system comprises stroke, anxiety, epilepsy, head trauma, migraine, pain, schizophrenia, affective disorders, addiction, and any combination thereof. 
     
     
         26 . The method of  claim 24 , wherein the subject is a human. 
     
     
         27 . The method of  claim 24 , wherein the interfering molecule is capable of permeating the blood brain barrier. 
     
     
         28 . The method of  claim 24 , wherein the interfering molecule inhibits the physical interaction of TrkB and PLCγ1. 
     
     
         29 . The method of  claim 24 , wherein the interfering molecule is capable of permeating the blood brain barrier. 
     
     
         30 . The method of  claim 24 , wherein the phosphopeptide comprises the amino acid sequence set forth in SEQ ID NO: 3. 
     
     
         31 . The method of  claim 24 , wherein the phosphopeptide comprises the amino acid sequence set forth in SEQ ID NO: 5. 
     
     
         32 . An isolated phosphopeptide comprising the amino acid sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 5. 
     
     
         33 . A pharmaceutical composition in unit dosage form comprising per unit dosage a range of from about 0.01 mg to about 1000 mg of the isolated phosphopeptide of  claim 32  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         34 . The pharmaceutical composition to  claim 33 , wherein the range is from about 1 mg to about 500 mg. 
     
     
         35 . A kit useful for the treatment of a disorder of the nervous system in a subject, the kit comprising: a therapeutically effective amount of the pharmaceutical composition of  claim 33  and instructions for use.