T. cruzi-derived neurotrophic agents and methods of use therefor

Abstract

The invention relates to T. cruzi trans-sialidase (TS) and to the neurotrophic and IL-6 secretion-inducing activities of the protein. TS, neurotrophic variants and/or neurotrophic peptides based upon the sequence of TS can be administered to a mammal to directly or indirectly provide neurotrophic support for neurons. A mammalian neurotrophic factor (e.g., CNTF, LIF) can be co-administered with the TS, neurotrophic variant and/or neurotrophic peptide. TS, IL-6 secretion-inducing variants and/or IL-6 secretion-inducing peptides based upon the sequence of TS can be administered to a mammal to induce the secretion of IL-6. TS, active variants and/or active peptides can be administered to a mammal having an acquired or congenital condition characterized by neuronal degeneration or to a mammal that has experienced trauma to the brain, spinal cord or peripheral nerves.

1 - 26 . (canceled) 
     
     
         27 . A method of providing trophic support for neurons in a mammal, comprising administering to said mammal a therapeutically effective amount of  T. Cruzi  trans-sialidase (TS) or a neurotrophic variant thereof, wherein the neurotrophic variant comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:12, 13, 14, 15, 16 and an amino acid sequence in which SEQ ID NO:32 occurs at least twice, whereby neurotrophic support is provided. 
     
     
         28 . The method of  claim 27 , further comprising co-administering a mammalian neurotrophic factor. 
     
     
         29 . The method of  claim 28 , wherein said mammalian neurotrophic factor is cilliary neurotrophic factor (CNTF) or leukemia inhibitory factor (LIF). 
     
     
         30 . The method of  claim 27 , wherein said neurotrophic variant comprises the amino acid sequence of peptide C44 (SEQ ID NO:12). 
     
     
         31 . The method of  claim 27 , wherein said neurotrophic variant comprises the amino acid sequence of peptide C14 (SEQ ID NO:14). 
     
     
         32 . The method of  claim 27 , wherein said neurotrophic variant is a fusion protein comprising
 i) an amino acid sequence selected from the group consisting of SEQ ID NOs:12, 13, 14, 15, 16 and an amino acid sequence in which SEQ ID NO:32 occurs at least twice; and   ii) a fusion partner, wherein said fusion partner is a mammalian neurotrophic factor.   
     
     
         33 . The method of  claim 32 , wherein said fusion protein comprises the amino acid sequence of peptide C14 (SEQ ID NO:14). 
     
     
         34 . The method of  claim 32 , wherein said fusion protein comprises an amino acid sequence in which the amino acid sequence of peptide TR1 (SEQ ID NO:32) occurs at least twice. 
     
     
         35 . The method of  claim 32 , wherein said neurotrophic factor is nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), interleukin-6 (IL-6), interleukin-11 (IL-11), leukemia inhibitory factor (LIF), cilliary neurotrophic factor (CNTF), or oncostatin-M (OSM). 
     
     
         36 . The method of  claim 35 , wherein said neurotrophic factor is CNTF or LIF. 
     
     
         37 . The method of  claim 27 , wherein said mammal has a condition selected from the group consisting of amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, Chagas' disease, peripheral neuropathy, palsies, multiple sclerosis, stroke, brain trauma, spinal cord trauma and peripheral nerve trauma. 
     
     
         38 . The method of  claim 27 , wherein said mammal is a human. 
     
     
         39 . A method of providing trophic support for neurons in a mammal, comprising administering to said mammal a therapeutically effective amount of a peptide comprising the amino acid sequence of peptide C14 (SEQ ID NO:14). 
     
     
         40 . The method of  claim 39 , further comprising co-administering a mammalian neurotrophic factor. 
     
     
         41 . The method of  claim 40 , wherein said neurotrophic factor is cilliary neurotrophic factor (CNTF) or leukemia inhibitory factor (LIF). 
     
     
         42 . The method of  claim 39 , wherein said peptide further comprises an amino-terminal protecting group, a carboxyl-terminal protecting group or a combination thereof. 
     
     
         43 . The method of  claim 39 , wherein said mammal has a condition selected from the group consisting of amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, Chagas' disease, peripheral neuropathy, palsies, multiple sclerosis, stroke, brain trauma, spinal cord trauma and peripheral nerve trauma. 
     
     
         44 . The method of  39 , wherein said mammal is a human. 
     
     
         45 . A method of stimulating the secretion of interleukin-6 in a mammal, comprising administering to said mammal a therapeutically effective amount of  T. cruzi  trans-sialidase (TS) or an IL-6 secretion-inducing variant thereof; wherein the IL-6 secretion-inducing variant comprises an amino acid sequence in which SEQ ID NO:32 occurs at least twice, whereby interleukin-6 secretion is stimulated. 
     
     
         46 . The method of  claim 45 , wherein said variant is a fusion protein comprising
 i)  T. cruzi  trans-sialidase (TS) or an IL-6 secretion-inducing variant thereof, wherein the IL-6 secretion-inducing variant comprises an amino acid sequence in which SEQ ID NO:32 occurs at least twice; and   ii) a fusion partner, wherein said fusion partner is a mammalian neurotrophic factor.   
     
     
         47 . The method of  claim 45 , wherein said mammal is a human. 
     
     
         48 . A method of stimulating the secretion of interleukin-6 in a mammal, comprising administering to said mammal a therapeutically effective amount of a peptide comprising an amino acid sequence in which the amino acid sequence of peptide TR1 (SEQ ID NO:32) occurs at least twice. 
     
     
         49 . The method of  claim 48 , wherein said peptide further comprises an amino-terminal protecting group, a carboxyl-terminal protecting group or a combination thereof. 
     
     
         50 . A method of providing trophic support for glial cells in a mammal, comprising administering to said mammal a therapeutically effective amount of  T. Cruzi  trans-sialidase (TS) or a neurotrophic variant thereof; wherein the neurotrophic variant comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:12, 13, 14, 15, 16 and an amino acid sequence in which SEQ ID NO:32 occurs at least twice, whereby neurotrophic support is provided. 
     
     
         51 . A method of providing trophic support for glial cells in a mammal, comprising administering to said mammal a therapeutically effective amount of a peptide comprising the amino acid sequence of peptide C14 (SEQ ID NO:14).