Treatment of sanfilippo syndrome type b by intrathecal administration of alpha-n-acetylglucosaminidase

Patent metadata

Field	Value
Publication number	US-9814764-B2
Application number	US-201313892076-A
Country	US
Kind code	B2
Filing date	May 10, 2013
Priority date	Jun 25, 2010
Publication date	Nov 14, 2017
Grant date	Nov 14, 2017

Abstract

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.

First claim

We claim:

1. A method of treating Sanfilippo syndrome type B (San B) disease comprising the steps of:
intrathecally administering to a subject in need of treating San B disease a pharmaceutical composition comprising a recombinant fusion protein,
wherein the recombinant fusion protein comprises a lysosomal targeting moiety, an alpha-N-acetylglucosaminidase (Naglu) domain, 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 90% sequence identity to the amino acid sequence of SEQ ID NO: 1, and
wherein the linker comprises the amino acid sequence of GAPGGGGGAAAAAGGGGGGAPGGGGGGAAAAAGGGGGGAPGGGGGAAAAAGGGGG GAP, which is residues 721-777 of SEQ ID NO:6.

2. The method of claim 1 , wherein the lysosomal targeting moiety is fused via the linker to the C-terminus of the Naglu domain.

3. The method of claim 1 , wherein the lysosomal targeting moiety is fused via the linker to the N-terminus of the Naglu domain.

4. The method of claim 1 , wherein the recombinant fusion protein is produced and isolated from human cells.

5. The method of claim 1 , wherein the intrathecal administration results in delivery of the recombinant fusion protein in one or more target brain tissues.

6. The method of claim 5 , wherein the one or more target brain tissues are selected from the group consisting of tissues from gray matter, white matter, periventricular areas, pia-arachnoid, meninges, neocortex, cerebellum, deep tissues in cerebral cortex, molecular layer, caudate/putamen region, midbrain, deep regions of the pons or medulla, and combinations thereof.

7. The method of claim 5 , wherein the recombinant fusion protein is delivered to neurons, glial cells, perivascular cells and/or meningeal cells.

8. The method of claim 1 , wherein the recombinant fusion protein is delivered to neurons in the spinal cord.

9. The method of claim 1 , wherein the intrathecal administration results in systemic delivery of the recombinant fusion protein in peripheral target tissues.

10. The method of claim 1 , wherein the intrathecal administration results in lysosomal localization in brain target tissues, spinal cord neurons and/or peripheral target tissues.

11. The method of claim 10 , wherein the intrathecal administration results in reduction of lysosomal storage in the brain target tissues, spinal cord neurons and/or peripheral target tissues.

12. The method of claim 10 , wherein the intrathecal administration results in increased Naglu enzymatic activity in the brain target tissues, spinal cord neurons and/or peripheral target tissues.

13. The method of claim 1 , wherein the intrathecal administration is used in conjunction with intravenous administration.

14. The method of claim 1 , wherein the intrathecal administration is used in the absence of intravenous administration.

15. The method of claim 1 , wherein the intrathecal administration is used in the absence of concurrent immunosuppressive therapy.

16. The method of claim 1 , wherein said pharmaceutical composition comprises a surfactant.

17. The method of claim 16 , wherein said surfactant is present in the pharmaceutical composition at a concentration from 0.001-0.5%.

18. The method of claim 16 , wherein said surfactant is present in the pharmaceutical composition at a concentration of 0.2%.

19. The method of claim 16 , wherein said surfactant is a poloxamer.

20. The method of claim 19 , wherein the poloxamer is poloxamer 188.

Assignees

• Shire Human Genetic Therapies

Inventors

• Concino Michael F
• Calias Pericles
• Pan Jing
• Holmes Kevin
• Martini Paolo
• Romashko Alla
• Meiyappan Muthuraman
• Zhang Bohong
• Iskenderian Andrea
• Lundberg Dianna
• Norton Angela
• Strack-Logue Bettina
• Yan Huang
• Alessandrini Mary
• Pfeifer Richard

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P39/02

  Antidotes · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P43/00

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