US2009247457A1PendingUtilityA1

Neurotrophic components of the adnf i complex

Assignee: SECRETARY OF THE DEPTARTMENT OPriority: Sep 12, 2001Filed: Aug 25, 2008Published: Oct 1, 2009
Est. expirySep 12, 2021(expired)· nominal 20-yr term from priority
A61P 25/32A61P 25/00A61P 25/28A61P 15/00C07K 14/475A61K 38/00
52
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Claims

Abstract

This invention relates to Activity Dependent Neurotrophic Factor I complex (ADNF I complex) and polypeptides of this complex, which produce their neurotrophic effects through multiple proteases intrinsic to the ADNF I complex. The invention also relates to pharmaceutical compositions comprising ADNF I complex polypeptides, as well as methods for reducing neuronal cell death in vitro and in vivo, methods for treating oxidative stress in a patient, methods for reducing a condition associated with fetal alcohol syndrome in a subject, and methods of enhancing learning and memory both pre- and post-natally, all of which methods use the ADNF I complex polypeptides of the invention.

Claims

exact text as granted — not AI-modified
1 - 17 . (canceled) 
     
     
         18 . A method for reducing neuronal cell death, the method comprising contacting the neuronal cells with an Activity Dependent Neurotrophic Factor I complex (ADNF I) polypeptide in an amount sufficient to prevent neuronal cell death, wherein the ADNF I complex polypeptide comprises an amino acid sequence or a fragment thereof selected from the group consisting of: 
       
         
           
                 
                 
                 
               
                   WSDVGVSSGSAPDAFK 
                   (SEQ ID NO:1) 
                     
                 
                     
                 
                   NNSTTYAPISANVSTALGSTAALPTAAGPV 
                   (SEQ ID NO:2) 
                 
                     
                 
                   NFLTSHYSAANSVVGGTNPGK 
                   (SEQ ID NO:3) 
                 
                     
                 
                   NPSGTDWLNTNNQANPFN 
                   (SEQ ID NO:4) 
                 
                     
                 
                   LVPLTPINR 
                   (SEQ ID NO:5) 
                 
                     
                 
                   VLQAVXGADSNVAFQGKVIYRSESSGTSELLTR 
                   (SEQ ID NO:6) 
                 
                     
                 
                   GPTADITLTK 
                   (SEQ ID NO:7) 
                 
                     
                 
                   GTPTGXGPLIQ 
                   (SEQ ID NO:8) 
                 
                     
                 
                   VDPASGYPIVGYT 
                   (SEQ ID NO:9) 
                 
                     
                 
                   PSGTDWLNT 
                   (SEQ ID NO:10) 
                 
                   and 
                 
                     
                 
                   SESSGTSELLTR. 
                   (SEQ ID NO:11) 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         19 . The method of  claim 18 , wherein the ADNF I complex polypeptide comprises at least one D-amino acid. 
     
     
         20 . The method of  claim 18 , wherein the ADNF I complex polypeptide comprises all D-amino acids. 
     
     
         21 . The method of  claim 18 , wherein the neuronal cells are selected from the group consisting of spinal cord neurons, hippocampal neurons, cerebral cortical neurons and cholinergic neurons. 
     
     
         22 . The method of  claim 18 , wherein the neuronal cell death is in a patient infected with immunodeficiency virus. 
     
     
         23 . The method of  claim 22 , wherein the immunodeficiency virus is a human immunodeficiency virus. 
     
     
         24 . The method of  claim 18 , wherein the neuronal cell death is associated with excito-toxicity induced by N-methyl-D-aspartate stimulation. 
     
     
         25 . The method of  claim 18 , wherein the neuronal cell death is induced by the beta-amyloid peptide in a patient afflicted with Alzheimer's disease. 
     
     
         26 . The method of  claim 18 , wherein the neuronal cell death is induced by cholinergic blockade in a patient afflicted with Alzheimer's disease, the cholinergic blockade resulting in learning impairment. 
     
     
         27 . A method for treating oxidative stress in a patient, the method comprising administering to the patient an Activity Dependent Neurotrophic Factor I complex (ADNF I) polypeptide in an amount sufficient to reduce oxidative stress, wherein the ADNF I complex polypeptide comprises an amino acid sequence or a fragment thereof selected from the group consisting of: 
       
         
           
                 
                 
                 
               
                   WSDVGVSSGSAPDAFK 
                   (SEQ ID NO:1) 
                     
                 
                     
                 
                   NNSTTYAPISANVSTALGSTAALPTAAGPV 
                   (SEQ ID NO:2) 
                 
                     
                 
                   NFLTSHYSAANSVVGGTNPGK 
                   (SEQ ID NO:3) 
                 
                     
                 
                   NPSGTDWLNTNNQANPFN 
                   (SEQ ID NO:4) 
                 
                     
                 
                   LVPLTPINR 
                   (SEQ ID NO:5) 
                 
                     
                 
                   VLQAVXGADSNVAFQGKVIYRSESSGTSELLTR 
                   (SEQ ID NO:6) 
                 
                     
                 
                   GPTADITLTK 
                   (SEQ ID NO:7) 
                 
                     
                 
                   GTPTGXGPLIQ 
                   (SEQ ID NO:8) 
                 
                     
                 
                   VDPASGYPIVGYT 
                   (SEQ ID NO:9) 
                 
                     
                 
                   PSGTDWLNT 
                   (SEQ ID NO:10) 
                 
                   and 
                 
                     
                 
                   SESSGTSELLTR. 
                   (SEQ ID NO:11) 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         28 . The method of  claim 27 , wherein the ADNF I complex polypeptide comprises at least one D-amino acid. 
     
     
         29 . The method of  claim 27 , wherein the ADNF I complex polypeptide comprises all D-amino acids. 
     
     
         30 . A method for reducing a condition associated with fetal alcohol syndrome in a subject who is exposed to alcohol in utero, the method comprising administering to the subject an ADNF I complex polypeptide in an amount sufficient to reduce the condition associated with fetal alcohol syndrome, wherein the ADNF I complex polypeptide comprises an amino acid sequence or a fragment thereof selected from the group consisting of: 
       
         
           
                 
                 
                 
               
                   WSDVGVSSGSAPDAFK 
                   (SEQ ID NO:1) 
                     
                 
                     
                 
                   NNSTTYAPISANVSTALGSTAALPTAAGPV 
                   (SEQ ID NO:2) 
                 
                     
                 
                   NFLTSHYSAANSVVGGTNPGK 
                   (SEQ ID NO:3) 
                 
                     
                 
                   NPSGTDWLNTNNQANPFN 
                   (SEQ ID NO:4) 
                 
                     
                 
                   LVPLTPINR 
                   (SEQ ID NO:5) 
                 
                     
                 
                   VLQAVXGADSNVAFQGKVIYRSESSGTSELLTR 
                   (SEQ ID NO:6) 
                 
                     
                 
                   GPTADITLTK 
                   (SEQ ID NO:7) 
                 
                     
                 
                   GTPTGXGPLIQ 
                   (SEQ ID NO:8) 
                 
                     
                 
                   VDPASGYPIVGYT 
                   (SEQ ID NO:9) 
                 
                     
                 
                   PSGTDWLNT 
                   (SEQ ID NO:10) 
                 
                   and 
                 
                     
                 
                   SESSGTSELLTR. 
                   (SEQ ID NO:11) 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         31 . The method of  claim 30 , wherein the condition is selected from the group consisting of: a decreased body weight of a subject; a decreased brain weight of the subject; a decreased level of VIP mRNA of a subject; and death of a subject in utero. 
     
     
         32 . The method of  claim 30 , wherein the ADNF I complex polypeptide comprises at least one D-amino acid. 
     
     
         33 . The method of  claim 30 , wherein the ADNF I complex polypeptide comprises all D-amino acids. 
     
     
         34 - 45 . (canceled) 
     
     
         46 . A method for improving learning and/or memory in a subject, the method comprising the step of administering prenatally to the subject an Activity Dependent Neurotrophic Factor I complex (ADNF I) polypeptide in an amount sufficient to improve postnatal learning and/or memory of the subject, wherein the ADNF I complex polypeptide comprises an amino acid sequence or a fragment thereof selected from the group consisting of: 
       
         
           
                 
                 
                 
               
                   WSDVGVSSGSAPDAFK 
                   (SEQ ID NO:1) 
                     
                 
                     
                 
                   NNSTTYAPISANVSTALGSTAALPTAAGPV 
                   (SEQ ID NO:2) 
                 
                     
                 
                   NFLTSHYSAANSVVGGTNPGK 
                   (SEQ ID NO:3) 
                 
                     
                 
                   NPSGTDWLNTNNQANPFN 
                   (SEQ ID NO:4) 
                 
                     
                 
                   LVPLTPINR 
                   (SEQ ID NO:5) 
                 
                     
                 
                   VLQAVXGADSNVAFQGKVIYRSESSGTSELLTR 
                   (SEQ ID NO:6) 
                 
                     
                 
                   GPTADITLTK 
                   (SEQ ID NO:7) 
                 
                     
                 
                   GTPTGXGPLIQ 
                   (SEQ ID NO:8) 
                 
                     
                 
                   VDPASGYPIVGYT 
                   (SEQ ID NO:9) 
                 
                     
                 
                   PSGTDWLNT 
                   (SEQ ID NO:10) 
                 
                   and 
                 
                     
                 
                   SESSGTSELLTR. 
                   (SEQ ID NO:11) 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         47 . The method of  claim 46 , wherein the subject has normal mental capacity. 
     
     
         48 . The method of  claim 46 , wherein the subject has mental retardation, a family history of mental retardation, Down's syndrome, or a mother who is at least 35 years of age when pregnant with the subject. 
     
     
         49 . The method of  claim 48 , wherein mental retardation is not caused by consumption of alcohol by the subject's mother during pregnancy. 
     
     
         50 . The method of  claim 46 , wherein the ADNF I complex polypeptide is administered around the time of neural tube development and/or closure of the neural tube. 
     
     
         51 . The method of  claim 46 , wherein the ADNF I complex polypeptide is intraperitoneally administered to the mother during pregnancy. 
     
     
         52 . The method of  claim 46 , wherein the ADNF I complex polypeptide is orally or nasally administered to the mother during pregnancy. 
     
     
         53 . The method of  claim 46 , wherein the ADNF I complex polypeptide is encoded by a nucleic acid which is administered to the subject. 
     
     
         54 . The method of  claim 46 , wherein the ADNF I complex polypeptide comprises at least one D-amino acid. 
     
     
         55 . The method of  claim 46 , wherein the ADNF I complex polypeptide comprises all D-amino acids.

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