Reactivation of Axon Growth and Recovery in Chronic Spinal Cord Injury
Disclosed are methods of treating chronic nervous system diseases or injuries, e.g., chronic spinal cord injury, using Nogo receptor antagonists, including Nogo receptor-1 (NgR1) polypeptides, Nogo receptor-1 antibodies and antigen-binding fragments thereof, soluble Nogo receptors and fusion proteins thereof, and polynucleotides. Also disclosed are methods of noninvasively monitoring axonal growth during and after treatment with an axonal growth promoting agent.
1 . A method of treating chronic spinal cord injury in a mammal in need thereof, comprising administering to the mammal by bolus injection a therapeutically effective amount of a Nogo-receptor antagonist.
2 . A method for stimulating axonal growth following chronic spinal cord injury, comprising administering by bolus injection a therapeutically effective amount of a Nogo-receptor antagonist.
3 . The method of claim 1 , wherein said Nogo-receptor antagonist stimulates axonal growth.
4 . The method of claim 1 , wherein said chronic spinal cord injury is a spinal contusion.
5 . The method of claim 1 , wherein said Nogo-receptor antagonist is administered directly into the central nervous system, intracerebroventricularly, or intrathecally.
6 . The method of claim 1 , wherein said Nogo-receptor antagonist is administered parenterally or intraventricularly.
7 . The method of claim 1 , wherein the therapeutically effective amount is from 0.001 mg/kg to 10 mg/kg of Nogo-receptor antagonist.
8 . The method of claim 1 , wherein said Nogo-receptor antagonist is a Nogo receptor-1 polypeptide.
9 . The method of claim 8 , wherein said Nogo receptor-1 polypeptide is a soluble Nogo receptor-1 polypeptide.
10 . The method of claim 9 , wherein said soluble Nogo receptor-1 polypeptide is 90% identical to a reference amino acid sequence selected from the group consisting of:
(a) amino acids 26 to 310 of SEQ ID NO:10 or 11;
(b) amino acids 26 to 344 of SEQ ID NO:10 or 11;
(c) amino acids 26 to 445 of SEQ ID NO:10 or 11;
(d) amino acids 26 to 309 of SEQ ID NO:10 or 11;
(e) amino acids 27 to 310 of SEQ ID NO:10 or 11;
(f) amino acids 28 to 344 of SEQ ID NO:10 or 11;
(g) amino acids 29 to 445 of SEQ ID NO:10 or 11;
(h) amino acids 30 to 309 of SEQ ID NO:10 or 11;
(i) amino acids 1 to 310 of SEQ ID NO:10 or 11;
(j) amino acids 1 to 344 of SEQ ID NO:10 or 11;
(k) amino acids 1 to 445 of SEQ ID NO:10 or 11;
(l) amino acids 1 to 309 of SEQ ID NO:10 or 11; and
(m) a combination of one or more of said reference amino acid sequences.
11 . The method of claim 10 , wherein said soluble Nogo receptor-1 polypeptide is selected from the group consisting of:
(a) amino acids 26 to 310 of SEQ ID NO:10 or 11;
(b) amino acids 26 to 344 of SEQ ID NO:10 or 11;
(c) amino acids 26 to 445 of SEQ ID NO:10 or 11;
(d) amino acids 26 to 309 of SEQ ID NO:10 or 11;
(e) amino acids 27 to 310 of SEQ ID NO:10 or 11;
(f) amino acids 27 to 344 of SEQ ID NO:10 or 11;
(g) amino acids 27 to 445 of SEQ ID NO:10 or 11;
(h) amino acids 27 to 309 of SEQ ID NO:10 or 11;
(i) amino acids 1 to 310 of SEQ ID NO:10 or 11;
(j) amino acids 1 to 344 of SEQ ID NO:10 or 11;
(k) amino acids 1 to 445 of SEQ ID NO:10 or 11;
(l) amino acids 1 to 309 of SEQ ID NO:10 or 11; and
(m) a combination of one or more of said reference amino acid sequences.
12 . The method of claim 8 , wherein said Nogo receptor-1 polypeptide further comprises a non-NgR1 moiety.
13 . The method of claim 12 , wherein said non-NgR1 moiety is a heterologous polypeptide fused to said Nogo receptor-1 polypeptide.
14 . The method of claim 13 , wherein said heterologous polypeptide is selected from the group consisting of:
(a) serum albumin;
(b) an Fc region;
(c) a signal peptide;
(d) a polypeptide tag; and
(e) a combination of two or more of said heterologous polypeptides.
15 . The method of claim 12 , wherein said non-NgR1 moiety is a polymer conjugated to said Nogo receptor-1 polypeptide.
16 . The method of claim 8 , wherein said Nogo receptor-1 polypeptide is a cyclic polypeptide.
17 . The method of claim 1 , wherein said Nogo receptor antagonist comprises an antibody or antigen-binding fragment thereof that binds to a mammalian Nogo-receptor.
18 . The method of claim 1 , wherein said Nogo-receptor antagonist is an isolated polynucleotide selected from the group consisting of:
(a) an antisense polynucleotide;
(b) a ribozyme;
(c) a small interfering RNA (siRNA); and
(d) a small-hairpin RNA (shRNA).
19 . The method of claim 10 , wherein said Nogo receptor-1 polypeptide comprises a substitution of an amino acid with a different amino acid and wherein said substitution is at a position selected from the group consisting of: C266 of said reference amino acid sequence; C309 of said reference amino acid sequence; and C335 of said reference amino acid sequence.