Use of akt phosphorylation as a biomarker for prognosing neurodegenerative diseases and treating same

Abstract

The present invention relates to uses of a peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, analogues and derivatives thereof, for the treatment of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). The present invention further provides a method for assessing responsiveness to treatment with the peptide of the invention. In addition, the present invention relates to prognosis of ALS progression, using Akt and phosphorylated Akt as biomarkers.

1 . A method for prognosticating the progression of a neurodegenerative disease in a subject, comprising:
 (a) assessing the value of at least one marker selected from: pAkt and pAkt:tAkt ratio, in a bodily sample derived from the subject; and   (b) obtaining the ratio between the value of said marker and the value of the marker in a control sample,   wherein a level of pAkt or pAkt:tAkt ratio significantly below a control value indicates a rapid disease.   
     
     
         2 . The method according to  claim 1 , wherein the disease is selected from the group consisting of: amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS) and spinal muscular atrophy (SMA). 
     
     
         3 . The method according to  claim 1 , wherein the disease is amyotrophic lateral sclerosis (ALS). 
     
     
         4 . (canceled) 
     
     
         5 . The method according to  claim 1 , wherein the bodily sample is selected from the group consisting of: muscle, blood, blood plasma, lymph fluid, lymphocytes and leukocytes. 
     
     
         6 . The method according to  claim 1 , wherein the control value corresponds to pAkt level or pAkt:tAkt ratio in a sample selected from the group consisting of: a bodily sample of a healthy individual, a bodily sample of an individual not afflicted with any neurodegenerative disease, a bodily sample of an individual afflicted with a slowly progressing neurodegenerative disease and a sample derived from an ALS subject having a slow disease. 
     
     
         7 . A method for treating a neurodegenerative disease in a subject in need thereof, comprising administering to a subject having a rapidly progressing neurodegenerative disease a therapeutically effective amount of an agent capable of activating a Akt pathway, thereby treating the neurodegenerative disease. 
     
     
         8 . The method according to  claim 7 , wherein the disease is selected from the group consisting of: amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS) and spinal muscular atrophy (SMA). 
     
     
         9 . The method according to  claim 7 , wherein the disease is amyotrophic lateral sclerosis (ALS). 
     
     
         10 . (canceled) 
     
     
         11 . The method according to  claim 7 , wherein said agent capable of activating said Akt pathway comprises a peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2 and an analog or a derivative thereof. 
     
     
         12 - 13 . (canceled) 
     
     
         14 . The method according to  claim 7 , wherein determining a progression of the neurodegenerative disease is effected according to the method of  claim 1 . 
     
     
         15 . A method for treating a neurodegenerative disease in a subject in need thereof, comprising:
 (a) assessing the level of pAkt and pAkt:tAkt ratio in a bodily sample derived from the subject; and   (b) administering a therapeutically effective amount of a peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2 and an analog or a derivative thereof, to a subject having pAkt level or pAkt:tAkt ratio significantly below a control value.   
     
     
         16 . The method according to  claim 15 , wherein the disease is selected from the group consisting of: amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS) and spinal muscular atrophy (SMA). 
     
     
         17 . The method according to  claim 15 , wherein the disease is amyotrophic lateral sclerosis (ALS). 
     
     
         18 . The method according to  claim 15 , wherein the disease is selected from the group consisting of: Alzheimer's disease, Parkinson's disease, glaucoma, macular degeneration, hypoxia, fulminant toxic liver, kidney failure and infertility. 
     
     
         19 . The method according to  claim 15 , wherein the bodily sample is derived from the peripheral blood, the lymph system or a muscle of the subject. 
     
     
         20 . The method according to  claim 19 , wherein said peripheral blood or said lymph system comprises lymphocytes. 
     
     
         21 . The method according to  claim 15 , wherein the control value corresponds to pAkt level or pAkt:tAkt ratio in a sample selected from the group consisting of: a bodily sample of a healthy individual, a bodily sample of an individual not afflicted with any neurodegenerative disease, a bodily sample of an individual afflicted with a slowly progressing neurodegenerative disease and a sample derived from a ALS subject having a slow disease. 
     
     
         22 . The method according to  claim 15 , wherein the peptide is comprised in a pharmaceutical composition in combination with at least one more therapeutic drug. 
     
     
         23 . The method according to  claim 22 , wherein the at least one more therapeutic drug is selected from the group consisting of: an oxidative agent, non-halogen activated-oxygen compounds, non-oxygen activated-halogen compounds, N-halo compounds and riluzole. 
     
     
         24 - 26 . (canceled) 
     
     
         27 . The method according to  claim 15 , wherein the peptide consists of an amino acid sequence selected from SEQ ID NO: 1, SEQ ID NO: 2 and an analog or a derivative thereof. 
     
     
         28 . A method for treating amyotrophic lateral sclerosis (ALS) in a subject in need thereof, comprising:
 (a) assessing the level of pAkt and pAkt:tAkt ratio in bodily sample derived from the subject; and   (b) administering a therapeutically effective amount of a peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2 and an analog or a derivative thereof, to a subject having pAkt level or pAkt:tAkt ratio significantly below a control value.   
     
     
         29 . The method according to  claim 28 , wherein the bodily sample is derived from the peripheral blood, the lymph system or the muscle of the subject. 
     
     
         30 . The method according to  claim 29 , wherein said peripheral blood or said lymph system comprises lymphocytes. 
     
     
         31 . The method according to  claim 28 , wherein the control value corresponds to pAkt level or pAkt:tAkt ratio in a sample selected from the group consisting of: a bodily sample of a healthy individual, a bodily sample of an individual not afflicted with any neurodegenerative disease, a bodily sample of an individual afflicted with a slowly progressing neurodegenerative disease and a sample derived from a ALS subject having a slow disease. 
     
     
         32 . The method according to  claim 28 , wherein the peptide is comprised in a pharmaceutical composition in combination with at least one more therapeutic drug. 
     
     
         33 . The method according to  claim 32 , wherein the at least one more therapeutic drug is selected from the group consisting of: an oxidative agent, non-halogen activated-oxygen compounds, non-oxygen activated-halogen compounds, N-halo compounds and riluzole. 
     
     
         34 - 36 . (canceled) 
     
     
         37 . The method according to  claim 28 , wherein the peptide consists of an amino acid sequence selected from SEQ ID NO: 1, SEQ ID NO: 2 and an analog or a derivative thereof. 
     
     
         38 . A method for assessing responsiveness to treatment of a disease with a peptide comprising an amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2 or an analog or a derivative thereof, or a pharmaceutical composition comprising same, the method comprising: assessing the level of pAkt or pAkt:tAkt ratio in bodily sample derived from a subject, wherein responsiveness to treatment is indicated by a pAkt level or pAkt:tAkt ratio significantly above a value of a pAkt level or pAkt:tAkt ratio in said subject prior to said treatment. 
     
     
         39 . The method according to  claim 38 , wherein the disease is selected from the group consisting of amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS) and spinal muscular atrophy (SMA). 
     
     
         40 . The method according to  claim 38 , wherein the disease is amyotrophic lateral sclerosis (ALS). 
     
     
         41 . The method according to  claim 38 , wherein the bodily sample is derived from the peripheral blood, the lymph system or a muscle of said subject. 
     
     
         42 . The method according to  claim 41 , wherein said peripheral blood or said lymph system comprises lymphocytes. 
     
     
         43 . The method according to  claim 38 , wherein the control value corresponds to pAkt level or pAkt:tAkt ratio in a sample selected from the group consisting of: a bodily sample of a healthy individual, a bodily sample of an individual not afflicted with any neurodegenerative disease, a bodily sample of an individual afflicted with a slowly progressing neurodegenerative disease and a sample derived from a ALS subject having a slow disease. 
     
     
         44 - 53 . (canceled) 
     
     
         54 . A method of determining the efficacy of treatment of a neurodegenerative disease in a subject in need thereof comprising determining in a sample from the subject the effect of a peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2 on the level of pAkt and pAkt:tAkt ratio, wherein an increase in said level indicates that said subject is responsive to treatment with said peptide. 
     
     
         56 . The method according to  claim 54 , wherein the disease is amyotrophic lateral sclerosis (ALS). 
     
     
         57 . The method according to  claim 54 , wherein the sample is derived from the peripheral blood, the lymph system or a muscle of said subject and optionally wherein said peripheral blood or said lymph system comprises lymphocytes. 
     
     
         58 . (canceled)