Fusion proteins for the treatment of cns

Abstract

This disclosure relates to compositions capable of use in the treatment of spinal cord injuries and related disorders of the central nervous system (CNS), and in particular, compositions including proteoglycan degrading molecules and compositions capable of blocking and/or over coming the activity of neuronal growth inhibitory molecules, as well as fusion proteins which includes a proteoglycan degrading domain and a domain capable of blocking and or over coming the activity of neuronal growth inhibitory molecules.

1 - 45 . (canceled) 
     
     
         46 . A composition comprising:
 a polypeptide comprising a protein transduction domain and a proteoglycan degrading domain, wherein the proteoglycan degrading domain is selected from the group consisting of chondroitinase ABC I (SEQ ID NO: 50), chondroitinase ABC II (SEQ ID NO: 35), hyaluronidase-1 (SEQ ID NO: 38), hyaluronidase-2 (SEQ ID NO: 39), hyaluronidase-3 (SEQ ID NO: 40), hyaluronidase-4 (SEQ ID NO: 41), PH-20 (SEQ ID NO: 42), chondroitinase B (SEQ ID NO: 37), chondroitinase AC (SEQ ID NO: 36), and a combination thereof.   
     
     
         47 . The composition of  claim 46 , wherein the protein transduction domain is a TAT domain. 
     
     
         48 . The composition of  claim 46 , wherein the protein transduction domain and the proteoglycan degrading domain are bonded together by a linker polypeptide domain. 
     
     
         49 . The composition of  claim 46 , further comprising a pharmaceutically acceptable excipient. 
     
     
         50 . The composition of  claim 46 , wherein the polypeptide comprises an amino acid sequence represented by SEQ ID NO: 89. 
     
     
         51 . The composition of  claim 46 , further comprising cells from the central nervous system. 
     
     
         52 . The composition of  claim 46 , wherein the polypeptide further comprises a domain that promotes neural regeneration. 
     
     
         53 . The composition of  claim 52 , wherein the domain that promotes neural regeneration is selected from the group consisting of L1 (SEQ ID NO: 5), a functional variant that is at least 80% L1, a functional deletion mutant of L1, GGF2 (SEQ ID NO:6), a functional variant that is at least 80% GGF2, a functional deletion mutant of GGF2, NgR27-311 (SEQ ID NO:4), a functional variant that is at least 80% NgR27-311, and a functional deletion mutant of NgR27-311. 
     
     
         54 . The composition of  claim 52 , wherein the domain that promotes neural regeneration is bonded to the protein transduction domain or the proteoglycan degrading domain by a linker polypeptide domain. 
     
     
         55 . The composition of  claim 46 , wherein the proteoglycan degrading domain chondroitinase ABC I (SEQ ID NO: 50) does not comprise a signal sequence. 
     
     
         56 . A method of promoting recovery of neurological function comprising:
 administering to a subject in need thereof a composition comprising a polypeptide comprising a protein transduction domain and a proteoglycan degrading domain, wherein the proteoglycan degrading domain is selected from the group consisting of chondroitinase ABC I (SEQ ID NO: 50), chondroitinase ABC II (SEQ ID NO: 35), hyaluronidase-1 (SEQ ID NO: 38), hyaluronidase-2 (SEQ ID NO: 39), hyaluronidase-3 (SEQ ID NO: 40), hyaluronidase-4 (SEQ ID NO: 41), PH-20 (SEQ ID NO: 42), chondroitinase B (SEQ ID NO: 37), chondroitinase AC (SEQ ID NO: 36), and a combination thereof.   
     
     
         57 . The method of  claim 56 , wherein the protein transduction domain is a TAT domain. 
     
     
         58 . The method of  claim 56 , wherein the protein transduction domain and the proteoglycan degrading domain are bonded together by a linker polypeptide domain. 
     
     
         59 . The method of  claim 56 , wherein the composition further comprises a pharmaceutically acceptable excipient. 
     
     
         60 . The method of  claim 56 , wherein the polypeptide comprises an amino acid sequence represented by SEQ ID NO: 89. 
     
     
         61 . The method of  claim 56 , wherein the composition further comprises cells from the central nervous system. 
     
     
         62 . The method of  claim 56 , wherein the polypeptide further comprises a domain that promotes neural regeneration. 
     
     
         63 . The method of  claim 62 , wherein the domain that promotes neural regeneration is selected from the group consisting of L1 (SEQ ID NO: 5), a functional variant that is at least 80% L1, a functional deletion mutant of L1, GGF2 (SEQ ID NO: 6), a functional variant that is at least 80% GGF2, a functional deletion mutant of GGF2, NgR27-311 (SEQ ID NO: 4), a functional variant that is at least 80% NgR27-311, and a functional deletion mutant of NgR27-311. 
     
     
         64 . The method of  claim 62 , wherein the domain that promotes neural regeneration is bonded to the protein transduction domain or the proteoglycan degrading domain by a linker polypeptide domain. 
     
     
         65 . The method of  claim 56 , wherein the proteoglycan degrading domain chondroitinase ABC I (SEQ ID NO: 50) does not comprise a signal sequence.