METHODS AND COMPOSITIONS FOR CNS DELIVERY OF HEPARAN N-SULFATASE
The present invention provides, among other things, compositions and methods for CNS delivery of lysosomal enzymes for effective treatment of lysosomal storage diseases. In some embodiments, the present invention includes a stable formulation for direct CNS intrathecal administration comprising a heparan N-sulfatase (HNS) protein, salt, and a polysorbate surfactant for the treatment of Sanfilippo Syndrome Type A.
1 . A stable formulation for intrathecal administration comprising a heparan N-sulfatase (HNS) protein at a concentration at or greater than 5 mg/ml, and no greater than 50 mM phosphate.
2 . The stable formulation of claim 1 , wherein the HNS protein is present at a concentration up to approximately 100 mg/ml.
3 . The stable formulation of claim 1 , wherein the HNS protein is present at a concentration up to approximately 30 mg/ml.
4 . The stable formulation of claim 1 , wherein the HNS protein is present at a concentration ranging from approximately 10-20 mg/ml.
5 . The stable formulation of claim 1 , wherein the HNS protein is present at a concentration ranging of approximately 15 mg/ml.
6 . The stable formulation of claim 1 , wherein the HNS protein comprises an amino acid sequence of SEQ ID NO:1.
7 . The stable formulation of claim 1 , wherein the formulation further comprises NaCl.
8 . The stable formulation of claim 7 , wherein the NaCl is present at a concentration ranging from approximately 0-300 mM.
9 . The stable formulation of claim 8 , wherein the NaCl is present at a concentration of approximately 100-200 mM.
10 . The stable formulation of claim 9 , wherein the NaCl is present at a concentration of approximately 145 mM.
11 . The stable formulation of claim 1 , wherein the formulation further comprises a polysorbate surfactant.
12 . The stable formulation of claim 11 , wherein the polysorbate surfactant is polysorbate 20.
13 - 17 . (canceled)
18 . The stable formulation of claim 1 , wherein the phosphate is present at a concentration no greater than 20 mM.
19 . The stable formulation of claim 1 , wherein the phosphate is present at a concentration of approximately 5 mM.
20 . The stable formulation of claim 1 , wherein the formulation has a pH of approximately 5.0-8.0.
21 - 43 . (canceled)
44 . A method of treating Sanfilippo A Syndrome comprising a step of
administering intrathecally to a subject in need of treatment a formulation comprising a heparan N-sulfatase (HNS) protein at a concentration at or greater than 5 mg/ml, and no greater than 50 mM phosphate.
45 - 53 . (canceled)
54 . The method of claim 44 , wherein the intrathecal administration of the formulation results in reduction of lysosomal storage in the brain target tissues, spinal cord neurons and peripheral target tissues.
55 - 62 . (canceled)
63 . The method of claim 44 , wherein the intrathecal administration of the formulation results in reduced intensity, severity, or frequency, or delayed onset of at least one symptom or feature of the Sanfilippo A Syndrome.
64 - 67 . (canceled)
68 . The method of claim 44 , wherein the intrathecal administration is used in conjunction with intravenous administration.
69 - 71 . (canceled)
72 . The method of claim 44 , wherein the intrathecal administration is used in absence of concurrent immunosuppressive therapy.