Targeted therapeutic lysosomal enzyme fusion proteins and uses thereof
View Patent ↗The present invention relates in general to therapeutic fusion proteins useful to treat lysosomal storage diseases and methods for treating such diseases. Exemplary therapeutic fusion proteins comprise a lysosomal enzyme, a lysosomal targeting moiety, e.g., an IGF-II peptide, and a spacer peptide. Also provided are compositions and methods for treating Mucopolysaccharidosis Type IIIB (Sanfilippo B Syndrome), comprising a targeted therapeutic fusion protein comprising alpha-N-acetylglucosaminidase (Naglu), a lysosomal targeting moiety, e.g., an IGF-II peptide, and a spacer peptide.
1. A targeted therapeutic fusion protein comprising (i) a human α-N-acetylglucosaminidase (Naglu) protein comprising amino acids 1-743 or 24-743 of SEQ ID NO:1, (ii) a peptide tag comprising SEQ ID NO: 2 or amino acids 8-67 of SEQ ID NO:5and (iii) a spacer peptide located between the Naglu protein and the peptide tag, wherein the spacer peptide comprises the amino acid sequence GAPGGGSPAPAPTPAPAPTPAPAGGGPSGAP (SEQ ID NO: 51).
2. The targeted therapeutic fusion protein of claim 1 , wherein the peptide tag is an N-terminal tag or a C-terminal tag.
3. The targeted therapeutic fusion protein of claim 1 , wherein the peptide tag comprises amino acids 8-67 of SEQ ID NO:5.
4. The targeted therapeutic fusion protein of claim 1 , wherein the peptide tag comprises SEQ ID NO:2.
5. A pharmaceutical composition suitable for treating a lysosomal storage disease comprising the targeted therapeutic fusion protein of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
6. The targeted therapeutic fusion protein of claim 1 , wherein the peptide tag consists of amino acids 8-67 of SEQ ID NO:5.
7. The targeted therapeutic fusion protein of claim 1 , wherein the spacer peptide consists of the amino acid sequence of SEQ ID NO:51.
8. A targeted therapeutic fusion protein comprising (i) a human α-N-acetylglucosaminidase (Naglu) protein consisting of amino acids 1-743 or 24-743 of SEQ ID NO:1, (ii) a peptide tag consisting of SEQ ID NO:2 or amino acids 8-67 of SEQ ID NO:5 and (iii) a spacer peptide located between the Naglu protein and the peptide tag, wherein the spacer peptide consists of the amino acid sequence GAPGGGSPAPAPTPAPAPTPAPAGGGPSGAP (SEQ ID NO: 51).
9. The targeted therapeutic fusion protein of claim 8 that consists of (i) a human α-N-acetylglucosaminidase (Naglu) protein consisting of amino acids 24-743 of SEQ ID NO:1, (ii) a peptide tag consisting of amino acids 8-67 of SEQ ID NO:5 and (iii) a spacer peptide located between the Naglu protein and the peptide tag, wherein the spacer peptide consists of the amino acid sequence GAPGGGSPAPAPTPAPAPTPAPAGGGPS GAP (SEQ ID NO: 51).
10. The targeted therapeutic fusion protein of claim 8 that consists of (i) a human α-N-acetylglucosaminidase (Naglu) protein consisting of amino acids 24-743 of SEQ ID NO:1, (ii) a peptide tag consisting of SEQ ID NO:2 and (iii) a spacer peptide located between the Naglu protein and the peptide tag, wherein the spacer peptide consists of the amino acid sequence GAPGGGSPAPAPTPAPAPTPAPAGGGPSGAP (SEQ ID NO: 51).
11. A pharmaceutical composition suitable for treating a lysosomal storage disease comprising the targeted therapeutic fusion protein of claim 8 and a pharmaceutically acceptable carrier, diluent or excipient.
12. A pharmaceutical composition suitable for treating a lysosomal storage disease comprising the targeted therapeutic fusion protein of claim 9 and a pharmaceutically acceptable carrier, diluent or excipient.
13. A pharmaceutical composition suitable for treating a lysosomal storage disease comprising the targeted therapeutic fusion protein of claim 10 and a pharmaceutically acceptable carrier, diluent or excipient.
14. A method for treating Mucopolysaccharidosis Type IIIB (Sanfilippo B Syndrome) in a subject or reducing glycosaminoglycan levels in vivo comprising administering to the subject suffering from Sanfilippo B Syndrome a therapeutically effect amount of a pharmaceutical composition comprising a targeted therapeutic fusion protein comprising (i) a human α-N-acetylglucosaminidase (Naglu) protein comprising amino acids 1-743 or 24-743of SEQ ID NO: 1, (ii) a peptide tag comprising SEQ ID NO: 2 or amino acids 8-67 of SEQ ID NO: 5, and (iii) a spacer peptide located between the Naglu protein and the peptide tag, wherein the spacer peptide comprises the amino acid sequence GAPGGGSPAPAPTPAPAPTPAPAGGGPSGAP (SEQ ID NO: 51).
15. The method of claim 14 , wherein the peptide tag is an N-terminal tag or a C-terminal tag.
16. The method of claim 14 , wherein the peptide tag comprises amino acids 8-67 of SEQ ID NO: 5.
17. The method of claim 14 , wherein the peptide tag comprises SEQ ID NO: 2.
18. The method of claim 14 , wherein the effective amount is in the range of 2.5-20 mg per kilogram of body weight of the subject.
19. The method of claim 14 , wherein the pharmaceutical composition is administered intrathecally and/or intravenously.
20. The method of claim 19 , wherein the administering comprises introducing the pharmaceutical composition into a cerebral ventricle, lumbar area, or cisterna magna.
21. The method of claim 14 , wherein the pharmaceutical composition is administered intravenously.