Methods of promoting CNS neuronal repair by inhibiting LRP-1
This invention provides methods for promoting and/or restoring neurite outgrowth and neuronal regeneration by contacting an injured neuron with an inhibitor of low density lipoprotein receptor-related protein-1 (LRP-1).
1. A method of enhancing nerve growth or neuronal regeneration, comprising contacting a neuron with an inhibitor of low density lipoprotein receptor-related protein-1 (LRP-1) activity in the presence of a myelin-associated inhibitory protein, wherein the inhibitor of LRP-1 activity is a soluble extracellular ligand binding domain of LRP-1.
2. The method of claim 1 , wherein the neuron is a central nervous system neuron.
3. The method of claim 1 , wherein the neuron is in vitro.
4. The method of claim 1 , wherein the neuron is in vivo.
5. The method of claim 1 , wherein the myelin-associated inhibitory protein is selected from the group consisting of myelin associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), Nogo-A, Nogo-B, Nogo-C, ephrin-B3, Sema4D/CD100, repulsive guidance molecule b, and fragments thereof.
6. The method of claim 1 , wherein the soluble extracellular ligand binding domain of LRP-1 is selected from the group consisting of LRP-1(6-94) (SEQ ID NO:3), LRP-1(787-1164) (SEQ ID NO:4), LRP-1(804-1185) (SEQ ID NO:5), LRP-1(2462-2923) (SEQ ID NO:6), LRP-1(3274-3764) (SEQ ID NO:7) and LRP-1(3331-3778) (SEQ ID NO:8).
7. The method of claim 1 , wherein the soluble extracellular ligand binding domain of LRP-1 is attached to an immunoglobulin Fc domain.
8. The method of claim 1 , wherein the inhibitor of LRP-1 activity inhibits binding and/or endocytosis of myelin.
9. The method of claim 1 , wherein the inhibitor of LRP-1 activity inhibits myelin associated glycoprotein (MAG) activation of Rho or association with p75NTR.
10. The method of claim 1 , wherein the inhibitor of LRP-1 activity inhibits LRP-1 association with p75NTR.
11. A method of enhancing nerve growth or neuronal regeneration in a subject in need thereof, comprising administering to the subject an effective amount of an inhibitor of low density lipoprotein receptor-related protein-1 (LRP-1) activity, wherein the inhibitor of LRP-1 activity is a soluble extracellular ligand binding domain of LRP-1, and wherein the subject is human.
12. The method of claim 11 , wherein the subject has experienced an injury to the central nervous system.
13. The method of claim 12 , wherein the subject has experienced a spinal cord injury.
14. The method of claim 12 , wherein the subject has experienced a traumatic brain injury.
15. The method of claim 11 , wherein the soluble extracellular ligand binding domain of LRP-1 is selected from the group consisting of LRP-1(6-94) (SEQ ID NO:3), LRP-1(787-1164) (SEQ ID NO:4), LRP-1(804-1185) (SEQ ID NO:5), LRP-1(2462-2923) (SEQ ID NO:6), LRP-1(3274-3764) (SEQ ID NO:7) and LRP-1(3331-3778) (SEQ ID NO:8).
16. The method of claim 11 , wherein the soluble extracellular ligand binding domain of LRP-1 is attached to an immunoglobulin Fc domain.
17. The method of claim 11 , wherein the inhibitor of LRP-1 activity inhibits binding and/or endocytosis of myelin.
18. The method of claim 11 , wherein the inhibitor of LRP-1 activity inhibits myelin associated glycoprotein (MAG) activation of Rho or association with p75NTR.
19. The method of claim 11 , wherein the inhibitor of LRP-1 activity inhibits LRP-1 association with p75NTR.
20. The method of claim 12 , wherein the inhibitor of LRP-1 activity is administered directly to injury.