Methods of treating neurological disorders

Abstract

Disclosed is a method for treating a subject having a neurological disorder characterized by the presence of dipeptide repeat proteins comprising contacting the cerebrospinal fluid (CSF) of the subject with an agent capable of removing or degrading the toxic protein.

What is claimed is: 
     
         1 . A method of treating a neurological disorder characterized by the presence of a dipeptide repeat protein in cerebrospinal fluid (CSF), the method comprising contacting the CSF of a subject in need thereof with an effective amount of a protease capable of removing or degrading the dipeptide repeat protein, wherein the dipeptide repeat protein comprises two or more repeats of a dipeptide amino acid sequence. 
     
     
         2 . The method of  claim 1 , wherein the dipeptide amino acid sequence is selected from the group consisting of glycine-alanine (GA), glycine-arginine (GR), alanine-proline (AP), glycine-proline (GP), and proline-arginine (PR). 
     
     
         3 . The method of  claim 1 , wherein the dipeptide repeat protein is a mutant chromosome 9 open reading frame 72 (C9orf72) protein. 
     
     
         4 . The method of  claim 1 , wherein the protease is selected from the group consisting of trypsin, thrombin, proteinase K, elastase, Factor Xa, kallikreins, clostripains, calpains, cathepsins, and thermolysin. 
     
     
         5 . The method of  claim 1 , wherein neurological disorder is selected from the group consisting of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and frontotemporal lobar degeneration (FTLD). 
     
     
         6 . The method of  claim 1 , wherein the protease is contacted with the CSF in situ. 
     
     
         7 . The method of  claim 1 , wherein the protease is immobilized to a solid substrate. 
     
     
         8 . The method of  claim 7 , wherein the solid substrate is selected from the group consisting of porous solid substrate and cross-linked resin. 
     
     
         9 . The method of  claim 1 , further comprising the step of detecting the dipeptide repeat protein from the CSF of the subject. 
     
     
         10 . The method of  claim 9 , wherein the step of detection is conducted prior to the step of contacting, thereby identifying the subject as suitable for the treatment. 
     
     
         11 . A device comprising:
 a housing forming an interior; and   a protease within the interior;   the protease being in an effective amount capable of removing or degrading a dipeptide repeat protein in cerebrospinal fluid (“CSF”) of a subject in need thereof, wherein the dipeptide repeat protein comprises two or more repeats of a dipeptide amino acid sequence.   
     
     
         12 . The device of  claim 11 , further comprising a size filter that removes large biomolecules. 
     
     
         13 . The device of  claim 11 , further comprising at least one pump configured to produce flow for the CSF. 
     
     
         14 . The device of  claim 11 , wherein the protease is selected from the group consisting of trypsin, thrombin, proteinase K, elastase, Factor Xa, kallikreins, clostripains, calpains, cathepsins, and thermolysin. 
     
     
         15 . The device of  claim 11 , wherein the dipeptide amino acid sequence is selected from the group consisting of glycine-alanine (GA), glycine-arginine (GR), alanine-proline (AP), glycine-proline (GP), and proline-arginine (PR). 
     
     
         16 . The device of  claim 11 , wherein the subject has a neurological disorder characterized by the presence of dipeptide repeat protein and the neurological disorder is selected from the group consisting of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and frontotemporal lobar degeneration (FTLD). 
     
     
         17 . The device of  claim 16 , wherein the device is implanted into the subject. 
     
     
         18 . The device of  claim 17 , wherein the device is implanted into the subarachnoid space of the subject. 
     
     
         19 . A system comprising:
 a substrate; and   a protease immobilized with the substrate, the protease configured to removing or degrading a dipeptide repeat protein in cerebrospinal fluid (“CSF”) of a subject in need thereof, wherein the dipeptide repeat protein comprises two or more repeats of a dipeptide amino acid sequence.   
     
     
         20 . The system of  claim 19 , further comprising a size filter that removes large biomolecules. 
     
     
         21 . The system of  claim 19 , further comprising at least one pump configured to produce flow for the CSF. 
     
     
         22 . The system of  claim 19 , wherein the protease is selected from the group consisting of trypsin, thrombin, proteinase K, elastase, Factor Xa, kallikreins, clostripains, calpains, cathepsins, and thermolysin. 
     
     
         23 . The system of  claim 19 , wherein the dipeptide amino acid sequence is selected from the group consisting of glycine-alanine (GA), glycine-arginine (GR), alanine-proline (AP), glycine-proline (GP), and proline-arginine (PR). 
     
     
         24 . The system of  claim 19 , wherein the subject has a neurological disorder characterized by the presence of dipeptide repeat protein and the neurological disorder is selected from the group consisting of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and frontotemporal lobar degeneration (FTLD). 
     
     
         25 . A composition comprising a protease immobilized with a solid substrate, the protease being capable of degrading or removing a dipeptide repeat protein in cerebrospinal fluid (CSF) of a subject having a neurological disorder, wherein the dipeptide repeat protein comprises two or more repeats of a dipeptide amino acid sequence. 
     
     
         26 . The composition of  claim 25 , wherein the protease is selected from the group consisting of trypsin, thrombin, proteinase K, elastase, Factor Xa, kallikreins, clostripains, calpains, cathepsins, and thermolysin. 
     
     
         27 . The composition of  claim 25 , wherein the dipeptide amino acid sequence is selected from the group consisting of glycine-alanine (GA), glycine-arginine (GR), alanine-proline (AP), glycine-proline (GP), and proline-arginine (PR). 
     
     
         28 . The composition of  claim 25 , wherein the neurological disorder characterized by the presence of dipeptide repeat protein and the neurological disorder is selected from the group consisting of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and frontotemporal lobar degeneration (FTLD). 
     
     
         29 . The composition of  claim 25 , wherein the solid substrate is selected from the group consisting of porous solid substrate, and cross-linked resin. 
     
     
         30 . The composition of  claim 25 , wherein the dipeptide repeat protein is a mutant chromosome 9 open reading frame 72 (C9orf72) protein.