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 (a) a human α-N-acetylglucosaminidase (Naglu) protein comprising amino acids 1-743 or 24-743 of SEQ ID NO: 1, (b) a peptide tag having an amino acid sequence at least 70% identical to amino acids 8-67 of SEQ ID NO: 5 (mature human IGF-II) and (c) a spacer peptide between the lysosomal enzyme and the peptide tag, wherein the spacer peptide comprises the amino acid sequence of SEQ ID NO:47.
2. The targeted therapeutic fusion protein of claim 1 , wherein the spacer peptide consists of the amino acid sequence of SEQ ID NO:47.
3. The targeted therapeutic fusion protein of claim 1 , wherein the peptide tag comprises amino acids 8-67 of SEQ ID NO: 5 (mature human IGF-II).
4. The targeted therapeutic fusion protein of claim 1 , wherein the peptide tag comprises all of amino acids 8-67 of SEQ ID NO: 5 (mature human IGF-II) except for a mutation at residue 37.
5. The targeted therapeutic fusion protein of claim 4 , wherein the mutation at residue 37 is a substitution of alanine for arginine.
6. The targeted therapeutic fusion protein of claim 1 , wherein the peptide tag consists of all of amino acids 8-67 of SEQ ID NO: 5 (mature human IGF-II) except for a mutation at residue 37.
7. The targeted therapeutic fusion protein of claim 6 , wherein the mutation at residue 37 is a substitution of alanine for arginine.
8. A pharmaceutical composition comprising the targeted therapeutic fusion protein of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
9. A method for treating a lysosomal storage disease in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the targeted therapeutic fusion protein claim 1 .
10. The method of claim 9 , wherein the pharmaceutical composition is administered intrathecally.
11. A method for reducing glycosaminoglycan levels in a subject suffering from Mucopolysaccharidosis Type IIIB (Sanfilippo B Syndrome) comprising administering to said subject an effective amount of a pharmaceutical composition comprising the targeted fusion protein of claim 1 .
12. The method of claim 11 , wherein the pharmaceutical composition is administered intrathecally.