Compositions comprising receptor-associated protein (rap) variants specific for cr-containing proteins and uses thereof

Abstract

The present invention relates generally to receptor-selective variants of the low-density lipoprotein receptor-associated protein (RAP) and compositions thereof, methods of generating such variants and methods of using such receptor-selective RAP variant compositions for therapeutic purposes.

What is claimed is: 
     
         1 . A method of treating a lysosomal storage disease, a neurological disorder, a liver disorder, cancer, or osteoporosis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a polypeptide comprising an amino acid sequence that is at least 80% identical to amino acids 144-319 of SEQ ID NO:121; wherein the polypeptide contains at least one mutation within amino acid positions 205-319 of SEQ ID NO:121; to treat the lysosomal storage disease, the neurological disorder, the liver disorder, the cancer, or the osteoporosis, respectively. 
     
     
         2 . The method of  claim 1  for treating the lysosomal storage disease. 
     
     
         3 . The method of  claim 1  for treating the neurological disorder 
     
     
         4 . The method of  claim 3 , wherein the neurological disorder is Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, or amyotrophic lateral sclerosis. 
     
     
         5 . The method of  claim 1  for treating the liver disorder. 
     
     
         6 . The method of  claim 5 , wherein the liver disorder is hepatitis. 
     
     
         7 . The method of  claim 1  for treating the cancer. 
     
     
         8 . The method of  claim 7 , wherein the cancer is brain cancer or hepatocellular carcinoma. 
     
     
         9 . The method of  claim 1 , wherein the mutation is a replacement of an amino acid selected from the group consisting of A, C, D, E, G, I, K, L, M, N, P, Q, R, S, T, and V with an amino acid selected from the group consisting of F, Y, W, and H. 
     
     
         10 . The method of  claim 1 , wherein the mutation is within positions 205-250 of SEQ ID NO: 121. 
     
     
         11 . The method of  claim 10 , wherein the mutation is at position 205, 213, 217, 226, 230, 232, 239, 246, 249, or a combination of two or more thereof 
     
     
         12 . The method of  claim 1 , wherein the mutation is within positions 271-319 of SEQ ID NO: 121. 
     
     
         13 . The method of  claim 12 , wherein the mutation is at position 273, 287, 290, 294, 296, 297, 298, 305, 312, 313, or a combination of two or more thereof. 
     
     
         14 . The method of  claim 1 , wherein the polypeptide further comprises a mutation in SEQ ID NO:121 at position 175, 251, 256, 257, 261, 266, 267, 268, 270, or a combination of two or more thereof. 
     
     
         15 . The method of  claim 1 , wherein the mutation is V175L, R205S, S213T, E217K, L226M, H249Y, E230V, S232P, E239G, E246G, E251L, E251K, E251T, E251G, E251P, E251N, E251R, K256R, K256V, K256A, K256I, K256P, K256L, 1266F, I266T, K257Y, Q261R, A267V, H268R, K270P, K270D, K270N, K270G, K270E, K270W, L271M, H273Y, D279Y, V283M, R287H, H290Y, H290L, E294V, R296L, T297I, K298R, K305T, K306M, S312F, G313D, or a combination of two or more thereof. 
     
     
         16 . A method of treating a lysosomal storage disease, a neurological disorder, a liver disorder, cancer, or osteoperosis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound comprising a therapeutic agent conjugated to a polypeptide, wherein the polypeptide comprises an amino acid sequence that is at least 80% identical to amino acids 144-319 of SEQ ID NO: 121; wherein the polypeptide contains at least one mutation within amino acid positions 205-319 of SEQ ID NO:121; to treat the lysosomal storage disease, the neurological disorder, the liver disorder, the cancer, or the osteoporosis, respectively. 
     
     
         17 . The method of  claim 16 , wherein the therapeutic agent is a glial cell-derived neuronal growth factor, a brain-derived neuronal growth factor, a neuronal growth factor, a disintegrin and metalloproteinase domain 10, a chaperone protein for LRP5/6, a chemotherapeutic agent, a protease inhibitor, a pro-apoptotic molecule, an autoimmune antigen, a lysosomal storage enzyme, a central nervous system depressant, a central nervous system stimulant, a psychopharmacological agent, a respiratory tract drug, a peripheral nervous system drug, a drug that acts at a synaptic or neuroeffector junctional site, a smooth muscle active drug, a histamine, an anti-histamine, a cardiovascular drug, a blood and hemopoietic system drug, a gastrointestinal drug, an anti-infective agent, an antibiotic agent, an antifungal agent, an antihelmitic agent, an antimalarial agent, an antiprotozoal agent, an anti-inflammatory agent, an immunosuppressive agent, an immunomodulatory agent, an analgesic agent, a cholinergic agent, an adrenergic agent, or a steroidal agent. 
     
     
         18 . The method of  claim 16 , wherein the mutation is within positions 205-250 of SEQ ID NO: 121; or wherein the mutation is within positions 271-319 of SEQ ID NO: 121 
     
     
         19 . A nucleic acid that encodes a polypeptide comprising an amino acid sequence that is at least 80% identical to amino acids 144-319 of SEQ ID NO:121; wherein the polypeptide contains at least one mutation within amino acid positions 205-319 of SEQ ID NO:121. 
     
     
         20 . The method of  claim 19 , wherein the mutation is within positions 205-250 of SEQ ID NO: 121; or wherein the mutation is within positions 271-319 of SEQ ID NO: 121.