STABLE FORMULATIONS FOR CNS DELIVERY OF ARYLSULFATASE A
The present invention provides, among other things, compositions and methods for CNS delivery of lysosomal enzymes (e.g., recombinant human arylsulfatase A (rhASA)) for effective treatment of lysosomal storage diseases (e.g., Metachromatic Leukodystrophy Disease). In some embodiments, the present invention includes a stable formulation for intrathecal administration comprising an ASA protein and a poloxamer, wherein less than 5% of the ASA protein exists in aggregated form.
1 - 47 . (canceled)
48 . A stable formulation for intrathecal administration comprising an arylsulfatase A (ASA) protein at a concentration of or greater than 5 mg/ml, poloxamer 188 and phosphate at a concentration of less than 5 mM.
49 . The stable formulation of claim 48 , wherein the ASA protein is present at a concentration selected from about 10 mg/ml, 30 mg/ml, 50 mg/ml, or 100 mg/ml.
50 . The stable formulation of claim 48 , wherein less than 5% of the arylsulfatase A (ASA) protein exists in aggregated form.
51 . The stable formulation of claim 48 , wherein the ASA protein is present at a concentration of at least 10 mg/ml.
52 . The stable formulation of claim 48 , wherein the ASA protein comprises the amino acid sequence of SEQ ID NO:1.
53 . The stable formulation of claim 48 , wherein the ASA protein is produced from a human cell line or from CHO cells.
54 . The stable formulation of claim 48 , wherein the formulation further comprises salt.
55 . The stable formulation of claim 54 , wherein the salt is NaCl and is present at a concentration of approximately 154 mM.
56 . The stable formulation of claim 48 , wherein the stable formulation further comprises a buffering agent selected from the group consisting of phosphate, acetate, histidine, succinate, citrate, Tris, and combinations thereof.
57 . The stable formulation of claim 56 , wherein the buffering agent is phosphate.
58 . The stable formulation of claim 48 , wherein the formulation is formulated as lyophilized dry powder.
59 . The stable formulation of claim 48 , wherein the formulation is a liquid formulation.
60 . The stable formulation of claim 48 , wherein the formulation further comprises a stabilizing agent selected from the group consisting of sucrose, glucose, mannitol, sorbitol, polyethylene glycol (PEG), histidine, arginine, lysine, phospholipids, trehalose and combination thereof.
61 . The stable formulation of claim 48 , wherein the stability of the ASA protein is maintained at room temperature.
62 . The stable formulation of claim 48 , wherein the stability of the ASA protein is maintained at 2-8° C.
63 . The stable formulation of claim 48 , wherein the stability of the ASA protein is maintained for a period of at least 12 months.
64 . A container comprising a single dosage form of a stable formulation according to claim 48 .
65 . A method of treating metachromatic leukodystrophy (MLD) disease comprising a step of administering intrathecally to a subject in need of treatment a formulation comprising an arylsulfatase A (ASA) protein at a concentration of or greater than 5 mg/ml, poloxamer 188 and phosphate at a concentration of less than 5 mM.