Therapeutic fusion protein comprising an alpha-n-acetylglucosaminidase and a lysosomal targeting moiety
Among other things, the present invention provides methods and compositions of treating Sanfilippo syndrome type B (Sanfilippo B) by, e.g., intrathecal (IT) administration of a Naglu protein. A suitable Naglu protein can be a recombinant, gene-activated or natural protein. In some embodiments, a suitable Naglu protein is a recombinant Naglu protein. In some embodiments, a recombinant Naglu protein is a fusion protein containing a Naglu domain and a lysosomal targeting moiety. In some embodiments, the lysosomal targeting domain is an IGF-II moiety.
1. A therapeutic fusion protein comprising
an alpha-N-acetylglucosaminidase (Naglu) domain;
a lysosomal targeting moiety, and
a linker between the lysosomal targeting moiety and the Naglu domain;
wherein the lysosomal targeting moiety is a peptide that binds cation-independent mannose-6-phosphate receptor (CI-MPR) or bis-phosphorylated oligosaccharides;
wherein the Naglu domain has alpha-N-acetylglucosaminidase activity and comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1;
wherein the linker comprises the amino acid sequence of residues 721-777 of SEQ ID NO: 6;
wherein once administered intrathecally, the therapeutic fusion protein is targeted to lysosomes.
2. The therapeutic fusion protein of claim 1 , wherein the lysosomal targeting moiety is an insulin-like growth factor-II (IGF-II) moiety.
3. The therapeutic fusion protein of claim 1 wherein the lysosomal targeting moiety is fused via the linker to the C-terminus of the Naglu domain.
4. A pharmaceutical composition comprising the therapeutic fusion protein of claim 1 and a surfactant.
5. The pharmaceutical composition of claim 4 , wherein the surfactant is present in the pharmaceutical composition at a concentration from 0.001-0.5%.
6. The pharmaceutical composition of claim 4 , wherein the surfactant is present in the pharmaceutical composition at a concentration of 0.2%.
7. The pharmaceutical composition of claim 4 , wherein the surfactant is a poloxamer.
8. The pharmaceutical composition of claim 7 , wherein the poloxamer is poloxamer 188.