Progranulin variants

Abstract

Provided herein are progranulin variants and fusion proteins that comprise a progranulin variant and an Fc polypeptide. Methods of using such proteins to treat progranulin-associated disorders (e.g., a neurodegenerative disease, such as frontotemporal dementia (FTD)) are also provided herein.

What is claimed is: 
     
         1 . A progranulin variant comprising an amino acid sequence having at least 90% identity to SEQ ID NO:2 and an amino acid sequence defined by X 1 X 2 X 3  at the positions corresponding to amino acid residues 574 to 576 of SEQ ID NO:2, wherein X 1 X 2 X 3  is selected from the group consisting of: PIL, PFL, PPL, PYL, QRL, and QHL. 
     
     
         2 . The progranulin variant of  claim 1 , wherein X 1 X 2 X 3  is PIL. 
     
     
         3 . The progranulin variant of  claim 1 , wherein the progranulin variant comprises the sequence of any one of SEQ ID NOS:13, 15, and 17-20. 
     
     
         4 . An Fc fusion polypeptide comprising a progranulin variant and an Fc polypeptide, wherein the progranulin variant comprises an amino acid sequence having at least 90% identity to SEQ ID NO:2 and an amino acid sequence defined by X 1 X 2 X 3  at the positions corresponding to amino acid residues 574 to 576 of SEQ ID NO:2, wherein X 1 X 2 X 3  is selected from the group consisting of: PIL, PFL, PPL, PYL, QRL, and QHL. 
     
     
         5 . The Fc fusion polypeptide of  claim 4 , wherein X 1 X 2 X 3  is PIL. 
     
     
         6 . The Fc fusion polypeptide of  claim 4 , wherein the progranulin variant comprises the sequence of any one of SEQ ID NOS:13, 15, and 17-20. 
     
     
         7 . The Fc fusion polypeptide of  claim 4 , wherein the Fc polypeptide is linked to the progranulin variant. 
     
     
         8 . The Fc fusion polypeptide of  claim 7 , wherein the Fc polypeptide is linked to the progranulin variant by a polypeptide linker comprising G 4 S (SEQ ID NO:90) or (G 4 S) 2  (SEQ ID NO:91). 
     
     
         9 . The Fc fusion polypeptide of  claim 7 , wherein the C-terminus of the Fc polypeptide is linked to the N-terminus of the progranulin variant. 
     
     
         10 . The Fc fusion polypeptide of  claim 4 , wherein the Fc polypeptide specifically binds to a transferrin receptor. 
     
     
         11 . A pharmaceutical composition comprising the progranulin variant of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         12 . A pharmaceutical composition comprising the Fc fusion polypeptide of  claim 4  and a pharmaceutically acceptable carrier. 
     
     
         13 . A method of treating a subject having a neurodegenerative disease, atherosclerosis, a disorder associated with TDP-43, age-related macular degeneration (AMD), or a progranulin-associated disorder, the method comprising administering the progranulin variant of  claim 1  to the subject. 
     
     
         14 . The method of  claim 13 , wherein the subject has a neurodegenerative disease selected from the group consisting of frontotemporal dementia (FTD), neuronal ceroid lipofuscinosis (NCL), Niemann-Pick disease type A (NPA), Niemann-Pick disease type B (NPB), Niemann-Pick disease type C (NPC), C90RF72-associated amyotrophic lateral sclerosis (ALS)/FTD, sporadic ALS, Alzheimer's disease (AD), Gaucher's disease, and Parkinson's disease. 
     
     
         15 . A method of treating a subject having a neurodegenerative disease, atherosclerosis, a disorder associated with TDP-43, age-related macular degeneration (AMD), or a progranulin-associated disorder, the method comprising administering the Fc fusion polypeptide of  claim 4  to the subject. 
     
     
         16 . The method of  claim 15 , wherein the subject has a neurodegenerative disease selected from the group consisting of frontotemporal dementia (FTD), neuronal ceroid lipofuscinosis (NCL), Niemann-Pick disease type A (NPA), Niemann-Pick disease type B (NPB), Niemann-Pick disease type C (NPC), C90RF72-associated amyotrophic lateral sclerosis (ALS)/FTD, sporadic ALS, Alzheimer's disease (AD), Gaucher's disease, and Parkinson's disease. 
     
     
         17 . A polynucleotide comprising a nucleic acid sequence encoding the progranulin variant of  claim 1 . 
     
     
         18 . A polynucleotide comprising a nucleic acid sequence encoding the Fc fusion polypeptide of  claim 4 . 
     
     
         19 . A vector comprising the polynucleotide of  claim 17 . 
     
     
         20 . A vector comprising the polynucleotide of  claim 18 . 
     
     
         21 . A host cell comprising the polynucleotide of  claim 17 . 
     
     
         22 . A host cell comprising the polynucleotide of  claim 18 . 
     
     
         23 . A host cell comprising the vector of  claim 19 . 
     
     
         24 . A host cell comprising the vector of  claim 20 . 
     
     
         25 . A method for producing a progranulin variant, comprising culturing the host cell of  claim 21  under conditions in which the progranulin variant encoded by the polynucleotide is expressed. 
     
     
         26 . A method for producing an Fc fusion polypeptide, comprising culturing the host cell of  claim 22  under conditions in which the Fc fusion polypeptide encoded by the polynucleotide is expressed. 
     
     
         27 . A method for producing a progranulin variant, comprising culturing the host cell of  claim 23  under conditions in which the progranulin variant encoded by the vector is expressed. 
     
     
         28 . A method for producing an Fc fusion polypeptide, comprising culturing the host cell of  claim 24  under conditions in which the Fc fusion polypeptide encoded by the vector is expressed.