Modulation of the Neuroendocrine System as a Therapy for Motor Neuron Disease

Abstract

The invention provides a method for treating amyotrophic lateral sclerosis (ALS) in a subject. The method comprises administering to the nervous system of the subject a composition comprising a thyroxine protein or a therapeutic fragment or pharmacologic mimic thereof and a pharmaceutically acceptable carrier. The invention also provides a method for treating ALS in a subject that comprises administering to the subject a transthyretin protein, 7B2 protein, a cystatin C protein, a neuroendocrine protein, a cysteine protease inhibitor, or an inhibitor of an enzyme that processes a 7B2 protein. In addition, the invention provides methods for determining the susceptibility of a subject to developing ALS and for determining the progression of ALS in a subject.

1 . A method for treating amyotrophic lateral sclerosis (ALS) in a subject, which method comprises administering to the nervous system of the subject a composition comprising a thyroxine protein or a therapeutic fragment or pharmacologic mimic thereof and a pharmaceutically acceptable carrier. 
     
     
         2 . A method for treating ALS in a subject, which method comprises administering to the subject a transthyretin protein. 
     
     
         3 . The method of  claim 2 , wherein the transthyretin protein is administered to the subject through a gene transfer vector comprising a nucleic acid sequence encoding the transthyretin protein operably linked to a promoter. 
     
     
         4 . The method of  claim 2 , wherein the transthyretin protein is administered to the subject through a composition comprising the transthyretin protein or a therapeutic fragment thereof and a pharmaceutically acceptable carrier. 
     
     
         5 . A method for treating ALS in a subject, which method comprises administering to the subject a 7B2 protein. 
     
     
         6 . The method of  claim 5 , wherein the 7B2 protein is administered to the subject through a gene transfer vector comprising a nucleic acid sequence encoding the 7B2 protein operably linked to a promoter. 
     
     
         7 . The method of  claim 5 , wherein the 7B2 protein is administered to the subject through a composition comprising the 7B2 protein or a therapeutic fragment thereof and a pharmaceutically acceptable carrier. 
     
     
         8 . A method for treating ALS in a subject, which method comprises administering to the subject an inhibitor of an enzyme that processes a 7B2 protein. 
     
     
         9 . The method of  claim 8 , wherein the enzyme is selected from the group consisting of furin and carboxypeptidase E. 
     
     
         10 . A method for treating ALS in a subject, which method comprises administering to the subject a cystatin C protein. 
     
     
         11 . The method of  claim 10 , wherein the cystatin C protein is administered to the subject through a gene transfer vector comprising a nucleic acid sequence encoding the cystatin C protein operably linked to a promoter. 
     
     
         12 . The method of  claim 5 , wherein the cystatin C protein is administered to the subject through a composition comprising the cystatin C protein or a therapeutic fragment thereof and a pharmaceutically acceptable carrier. 
     
     
         13 . A method for treating ALS in a subject, which method comprises administering to the subject a composition comprising a cysteine protease inhibitor and a pharmaceutically acceptable carrier. 
     
     
         14 . A method for treating ALS in a subject, which method comprises administering to the subject a composition comprising a neuroendocrine protein and a pharmaceutically acceptable carrier. 
     
     
         15 . The method of  claim 11 , wherein the neuroendocrine protein is selected from the group consisting of neuropeptide Y, somatostatin, galanin, and vasopressin. 
     
     
         16 . A method for determining the susceptibility of a subject to developing ALS, which method comprises (a) obtaining a sample from the subject, (b) isolating from the sample a transthyretin protein, and (c) determining the amino acid or nucleotide sequence of the protein, wherein a protein or nucleic acid molecule encoding a variant of the transthyretin protein indicates that the subject is susceptible to developing ALS. 
     
     
         17 . The method of  claim 16 , wherein the sample is selected from the group consisting of cerebrospinal fluid, blood serum, plasma, urine, and tissue. 
     
     
         18 . A method for determining progression of ALS in a subject, which method comprises: (a) obtaining a sample from the subject, (b) isolating from the sample a transthyretin protein, (c) analyzing the transthyretin protein from the sample by mass spectroscopy, and (d) determining a mass spectral profile for the sample, wherein the presence of a variant of a wild type transthyretin protein in the sample indicates progression of ALS in the animal. 
     
     
         19 . The method of  claim 18 , wherein the sample is selected from the group consisting of cerebrospinal fluid, blood serum, plasma, urine, and tissue. 
     
     
         20 . A method for determining progression of ALS in a subject, which method comprises: (a) obtaining a sample from the subject, (b) isolating from the sample a transthyretin protein, (c) analyzing the transthyretin protein levels from the sample, and (d) comparing the protein levels to transthyretin protein levels obtained from the same subject at an earlier time, wherein a change in the protein levels indicates progression of ALS in the subject. 
     
     
         21 . The method of  claim 20 , wherein the sample is selected from the group consisting of cerebrospinal fluid, blood serum, plasma, urine, and tissue. 
     
     
         22 . The method of  claim 20 , wherein the change is a decrease in the levels of transthyreitn protein. 
     
     
         23 . The method of  claim 20 , wherein the change is an increase in the levels of transthyreitn protein. 
     
     
         24 . The method of  claim 20 , wherein the samples are analyzed by mass spectroscopy. 
     
     
         25 . The method of  claim 20 , wherein the samples are analyzed using immunological techniques. 
     
     
         26 . The method of  claim 20 , wherein the samples are analyzed by ELISA. 
     
     
         27 . The method of  claim 20 , wherein the samples are analyzed by immunoblot. 
     
     
         28 - 36 . (canceled)