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 a sequence having at least 90% identity to SEQ ID NO:2 and a sequence defined by X 1 X 2 X 3  at the positions corresponding to residues 574 to 576 of SEQ ID NO:2, wherein X 1 , X 2,  and X 3  are each independently an amino acid and together are not QLL. 
     
     
         2 . The progranulin variant of  claim 1 , wherein the progranulin variant has the sequence of SEQ ID NO:3. 
     
     
         3 . The progranulin variant of  claim 1 , wherein X 1 X 2 X 3  is X 1 IL, X 1 FL, X 1 QL, PX 2 L, QX 2 L, or VX 2 L. 
     
     
         4 . The progranulin variant of  claim 1 , wherein X 1 X 2 X 3  is PIL, PFL, QQL, VVL, VTL, PPL, PYL, QHL, or QRL. 
     
     
         5 . The progranulin variant of  claim 1 , wherein the progranulin variant comprises the sequence of any one of SEQ ID NOS:9, 13, 17-20. 
     
     
         6 . A polypeptide comprising a progranulin variant of  claim 1 . 
     
     
         7 . The polypeptide of  claim 6 , wherein the progranulin variant has the sequence of SEQ ID NO:3. 
     
     
         8 . The polypeptide of  claim 6 , wherein X 1 X 2 X 3  is X 1 IL, X 1 FL, X 1 QL, PX 2 L, QX 2 L, or VX 2 L. 
     
     
         9 . The polypeptide of  claim 6 , wherein X 1 X 2 X 3  is PIL, PFL, QQL, VVL, VTL, PPL, PYL, QHL, or QRL. 
     
     
         10 . The polypeptide of  claim 6 , wherein the progranulin variant comprises the sequence of any one of SEQ ID NOS:9. 13, and 17-20. 
     
     
         11 . The polypeptide of  claim 6 , further comprising an Fc polypeptide that is linked to the progranulin variant. 
     
     
         12 . The polypeptide of  claim 11 , wherein the Fc polypeptide is a modified Fc polypeptide that specifically binds to a transferrin receptor. 
     
     
         13 . A fusion protein comprising:
 (a) a progranulin variant of  claim 1 ;   (b) a first Fc polypeptide that is linked to the progranulin variant of (a); and   (c) a second Fc polypeptide that forms an Fc polypeptide dimer with the first Fc polypeptide.   
     
     
         14 . The fusion protein of  claim 13 , wherein the first Fc polypeptide or the second Fc polypeptide specifically binds to a transferrin receptor. 
     
     
         15 . The fusion protein of  claim 13 , wherein:
 (i) the first Fc polypeptide comprises a T366W substitution and the second Fc polypeptide comprises T366S, L368A, and Y407V substitutions, according to EU numbering; or   (ii) the first Fc polypeptide comprises T366S, L368A, and Y407V substitutions and the second Fc polypeptide comprises a T366W substitution, according to EU numbering.   
     
     
         16 . The fusion protein of  claim 13 , wherein the first Fc polypeptide and/or the second Fc polypeptide independently comprises L234A and L235A substitutions, according to EU numbering. 
     
     
         17 . The fusion protein of  claim 13 , wherein the second Fc polypeptide comprises a sequence selected from the group consisting of SEQ ID NOS:70, 75, 80, 85, and 129-132. 
     
     
         18 . The fusion protein of  claim 13 , wherein the progranulin variant comprises the sequence of any one of SEQ ID NOS:9, 13, 17-20. 
     
     
         19 . The fusion protein of  claim 13 , wherein the first Fc polypeptide linked to the progranulin variant comprises the sequence of SEQ ID NO:98, and the second Fc polypeptide comprises the sequence of SEQ ID NO:75 or 130. 
     
     
         20 . The fusion protein of  claim 13 , wherein the first Fc polypeptide linked to the progranulin variant comprises the sequence of SEQ ID NO:99, and the second Fc polypeptide the sequence of SEQ ID NO:75 or 130. 
     
     
         21 . The fusion protein of  claim 13 , wherein the first Fc polypeptide linked to the progranulin variant comprises the sequence of SEQ ID NO:126, and the second Fc polypeptide comprises the sequence of SEQ ID NO:75 or 130. 
     
     
         22 . The fusion protein of  claim 13 , wherein the first Fc polypeptide linked to the progranulin variant comprises the sequence of SEQ ID NO:98, and the second Fc polypeptide comprises the sequence of SEQ ID NO:85 or 132. 
     
     
         23 . The fusion protein of  claim 13 , wherein the first Fc polypeptide linked to the progranulin variant comprises the sequence of SEQ ID NO:99, and the second Fc polypeptide the sequence of SEQ ID NO:85 or 132. 
     
     
         24 . A pharmaceutical composition comprising the progranulin variant of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         25 . A pharmaceutical composition comprising a plurality of the fusion protein of  claim 13  and a pharmaceutically acceptable carrier. 
     
     
         26 . The pharmaceutical composition of  claim 25 , wherein more than 50% of the plurality of the fusion protein comprises an intact C-terminus in the progranulin variant of the fusion protein. 
     
     
         27 . 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. 
     
     
         28 . The method of  claim 27 , 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), C9ORF72-associated amyotrophic lateral sclerosis (ALS)/FTD, sporadic ALS, Alzheimer's disease (AD), Gaucher's disease, and Parkinson's disease. 
     
     
         29 . A polynucleotide comprising a nucleic acid sequence encoding the progranulin variant of  claim 1 . 
     
     
         30 . A vector or host cell comprising the polynucleotide of  claim 29 .