Fusion proteins for delivery of gdnf to the cns

Abstract

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.

What is claimed is: 
     
         1 . A composition comprising a neurotherapeutic agent covalently linked to an antibody to a transferrin receptor that is capable of crossing the blood brain barrier (BBB), wherein the composition is capable of producing an average elevation of concentration in the brain of the neurotherapeutic agent of at least about 1 ng/gram brain following intravenous administration. 
     
     
         2 . The composition of  claim 1 , wherein the neurotherapeutic agent alone does not cross the BBB in a therapeutically effective amount following intravenous administration. 
     
     
         3 . The composition of  claim 2 , wherein the antibody is a monoclonal antibody (MAb). 
     
     
         4 . The composition of  claim 3 , wherein the MAb is a chimeric MAb. 
     
     
         5 . The composition of  claim 4 , wherein the chimeric antibody contains sufficient human sequences to avoid significant immunogenic reaction when administered to a human. 
     
     
         6 . The composition of  claim 1 , wherein the antibody and the neurotherapeutic agent are covalently linked by a peptide linker. 
     
     
         7 . The composition of  claim 1 , wherein the neurotherapeutic agent is a neurotrophin. 
     
     
         8 . The composition of  claim 7 , wherein the neurotrophin is selected from the group consisting of brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-4/5, fibroblast growth factor (FGF)-2 and other FGFs, neurotrophin (NT)-3, erythropoietin (EPO), hepatocyte growth factor (HGF), epidermal growth factor (EGF), transforming growth factor (TGF)-α, TGF-β, vascular endothelial growth factor (VEGF), interleukin-1 receptor antagonist (IL-1ra), ciliary neurotrophic factor (CNTF), glial-derived neurotrophic factor (GDNF), neurturin, platelet-derived growth factor (PDGF), heregulin, neuregulin, artemin, persephin, interleukins, granulocyte-colony stimulating factor (CSF), granulocyte-macrophage-CSF, netrins, cardiotrophin-1, hedgehogs, leukemia inhibitory factor (LIF), midkine, pleiotrophin, bone morphogenetic proteins (BMPs), netrins, saposins, semaphorins, and stem cell factor (SCF).