Wnt compositions and therapeutic uses of such compositions

Patent metadata

Field	Value
Publication number	US-9403885-B2
Application number	US-201213979368-A
Country	US
Kind code	B2
Filing date	Jan 11, 2012
Priority date	Jan 11, 2011
Publication date	Aug 2, 2016
Grant date	Aug 2, 2016

Abstract

The invention provides novel Wnt polypeptides that have enhanced solubility and improved biologic drug-like properties, and polynucleotides encoding the Wnt polypeptides of the invention. The Wnt polypeptides of the invention can be used therapeutically, such as, for example, in methods of preventing or treating muscle loss and/or promoting muscle hypertrophy and growth.

First claim

The invention claimed is:

1. A modified Wnt7a polypeptide comprising one or more amino acids that reduce lipidation of the Wnt7a polypeptide, wherein said modified Wnt7a polypeptide comprises an amino acid deletion, insertion, or substitution of Cys73 or Ser206.

2. The modified Wnt7a polypeptide of claim 1 , wherein the modified Wnt7a polypeptide activates a non-canonical Wnt signaling pathway.

3. A modified Wnt7a polypeptide having decreased lipidation relative to the lipidation of the Wnt7a polypeptide corresponding to any one of SEQ ID NOs: 2 and 6-11, wherein said modified Wnt7a polypeptide comprise an amino acid deletion, insertion, or substitution of Cvs73 or Ser206 of any one of SEQ ID NOs: 2 and 6-11.

4. The modified Wnt7a polypeptide of claim 3 ,
wherein the polypeptide comprises:
a) an amino acid deletion, insertion, or substitution at the amino acid position corresponding to position 73 of any one of SEQ ID NOs: 2 and 6-11;
b) an amino acid deletion, insertion, or substitution at the amino acid position corresponding to position 206 of any one of SEQ ID NOs: 2 and 6-11;
c) one or more amino acid deletions, insertions, or substitutions at the amino acid positions corresponding to positions 73 and 206 of any one of SEQ ID NOs: 2 and 6-11;
d) an Alanine at the amino acid position corresponding to position 73 or 206 of any one of SEQ ID NOs: 2 and 6-11; or
e) an Alanine at the amino acid positions corresponding to positions 73 and 206 of any of SEQ ID NOs: 2 and 6-11.

5. A polynucleotide encoding the modified Wnt7a polypeptide of claim 1 .

6. A vector comprising the polynucleotide of claim 5 .

7. A host cell comprising the vector of claim 6 .

8. A modified Wnt7a polypeptide produced by the host cell of claim 7 .

9. A composition comprising the polypeptide of claim 8 .

10. A method for treating or preventing muscle loss comprising administering to a subject a composition according to claim 9 .

11. The method of claim 10 , wherein the subject has or is at risk of having a disease or condition affecting muscle.

12. The method of claim 11 , wherein the degenerative disease is muscular dystrophy.

13. The method of claim 11 , wherein the disease or condition affecting muscle is a wasting disease, muscular attenuation, muscle atrophy, ICU-induced weakness, prolonged disuse, surgery-induced weakness, or a muscle degenerative disease.

14. A Wnt7a polypeptide comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 3-5, and 12-13.

15. A fusion polypeptide comprising a Wnt7a polypeptide according to claim 14 and a native signal peptide, a heterologous signal peptide, a hybrid of a native and a heterologous signal peptide, a heterologous protease cleavage site, an epitope tag or an immunoglobulin Fc region.

16. The fusion polypeptide of claim 15 , wherein the heterologous signal peptide is selected from the group consisting of:
a) a CD33 signal peptide, an immunoglobulin signal peptide, a growth hormone signal peptide, an erythropoietin signal peptide, an albumin signal peptide, a secreted alkaline phosphatase signal peptide, and a viral signal peptide; or
b) a CD33 signal peptide, an IgGκ signal peptide, and a IgGμ signal peptide.

17. The fusion polypeptide of claim 15 , comprising a heterologous protease cleavage site or an epitope tag.

18. The fusion polypeptide of claim 15 , wherein the fusion polypeptide comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 3-5 and 12-13, has increased production, secretion, or solubility compared to a corresponding native Wnt polypeptide as set forth in SEQ ID NOs: 2 and 6-11.

Assignees

• Lee Tom Tong
• Bennett Monica Hayhurst
• Fitch Michael J
• Flynn Peter
• Fate Therapeutics Inc

Inventors

• Lee Tom Tong
• Bennett Monica Hayhurst
• Fitch Michael J
• Flynn Peter

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P21/04

  for myasthenia gravis · CPC title

• A61P21/02

  Muscle relaxants, e.g. for tetanus or cramps · CPC title

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title

• C07K2319/41

  containing a Myc-tag · CPC title