FUSION PROTEINS FOR DELIVERY OF GDNF TO THE CNS
The invention provides compositions, methods, and kits for increasing transport of GDNF across the blood brain barrier while allowing its activity to remain substantially intact. The GDNF is transported across the blood brain barrier via one or more endogenous receptor-mediated transport systems.
1 .- 24 . (canceled)
25 . A fusion protein comprising an agent fused to a structure that crosses the blood brain barrier (BBB) by binding an endogenous BBB receptor, wherein both the structure and the agent each retain at least 30% of their activities, compared to their activities as separate entities, and wherein the fusion protein produces an average elevation of concentration of the agent in the brain of at least 5 ng/gram brain following administration.
26 . The fusion protein of claim 25 , wherein the structure is an endogenous ligand.
27 . The fusion protein of claim 25 , wherein the agent is fused to the carboxy-terminus of the structure that crosses the BBB.
28 . The fusion protein of claim 25 , wherein the agent is fused to the amino-terminus of the structure that crosses the BBB.
29 . The fusion protein of claim 25 , wherein the agent is a neurotrophin.
30 . The fusion protein of claim 25 , wherein the agent is a neurotherapeutic peptide.
31 . The fusion protein of claim 25 , wherein the structure is an antibody.
32 . The fusion protein of claim 31 , wherein the antibody is a monoclonal antibody (MAb).
33 . The fusion protein of claim 25 , wherein the BBB receptor is selected from the group consisting of the insulin receptor, transferrin receptor, leptin receptor, lipoprotein receptor, and the IGF receptor.
34 . The fusion protein of claim 25 , wherein the BBB receptor is the insulin receptor.
35 . The fusion protein of claim 34 , wherein the insulin receptor is the human insulin receptor.
36 . The fusion protein of claim 25 , wherein the agent has a molecular weight greater than about 400 Daltons.
37 . The fusion protein of claim 25 , wherein the BBB is the human BBB.
38 . A method for treating a CNS disorder in an individual comprising peripherally administering to the individual an effective amount of the fusion protein of claim 25 .
39 . The method of claim 38 , wherein the structure is an antibody to an insulin receptor.
40 . The method of claim 38 , wherein the agent is a neurotrophin.
41 . The method of claim 38 , wherein the administering is selected from the group consisting of oral, intravenous, intramuscular, subcutaneous, intraperitoneal, rectal, transbuccal, intranasal, transdermal, and inhalation administering.
42 . The method of claim 38 , wherein the CNS disorder is an acute CNS disorder.
43 . The method of claim 42 , wherein the acute CNS disorder is selected from the group consisting of spinal cord injury, brain injury, focal brain ischemia and global brain ischemia.
44 . The method of claim 38 , wherein the fusion protein is administered at a frequency of no greater than about once per week.
45 . The method of claim 38 , wherein the CNS disorder is a chronic disorder.
46 . The method of claim 45 , wherein the chronic disorder is selected from the group consisting of chronic neurodegenerative disease, retinal ischemia, and depression.
47 . The method of claim 46 , wherein the chronic neurodegenerative disease is selected from the group consisting of prion diseases, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, transverse myelitis, motor neuron disease, Pick's disease, tuberous sclerosis, lysosomal storage disorders, Canavan's disease, Rett's syndrome, spinocerebellar ataxias, Friedreich's ataxia, optic atrophy, and retinal degeneration.
48 . The method of claim 38 , wherein the individual is a human.