Stable formulations for CNS delivery of arylsulfatase A
The present invention provides, among oilier 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 3% of the ASA protein exists in aggregated form.
1. A stable formulation for intrathecal administration comprising an arylsulfatase A (ASA) protein at a concentration of or greater than 5 mg/ml and a poloxamer 188 at a concentration ranging from 0.1-0.15%, and phosphate at a concentration of less than 5 mM;
wherein said formulation has a pH of 6,
wherein less than 5% of the arylsulfatase A (ASA) protein exists in aggregated form, and
wherein the stability of the ASA protein is maintained after storage over a period of at least 6 months.
2. The stable formulation of claim 1 , 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.
3. The stable formulation of claim 1 , wherein less than 1% of the arylsulfatase A (ASA) protein exists in aggregated form.
4. The stable formulation of claim 1 , wherein the ASA protein is present at a concentration of at least 10 mg/ml.
5. The stable formulation of claim 1 , wherein the ASA protein comprises the amino acid sequence of SEQ ID NO:1.
6. The stable formulation of claim 1 , wherein the ASA protein is produced from a human cell line or from CHO cells.
7. The stable formulation of claim 1 , wherein the formulation further comprises salt.
8. The stable formulation of claim 7 , wherein the salt is NaCl and is present at a concentration of approximately 154 mM.
9. The stable formulation of claim 1 , wherein the formulation is formulated as lyophilized dry powder.
10. The stable formulation of claim 1 , wherein the formulation is a liquid formulation.
11. The stable formulation of claim 1 , 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.
12. The stable formulation of claim 1 , wherein the stability of the ASA protein is maintained at room temperature.
13. The stable formulation of claim 1 , wherein the stability of the ASA protein is maintained at 2-8° C.
14. The stable formulation of claim 1 , wherein the stability of the ASA protein is maintained for a period of at least 12 months.
15. A container comprising a single dosage form of a stable formulation according to claim 1 .
16. 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 at a concentration ranging from approximately 0.05-0.50%, NaCl at a concentration ranging from approximately 0-300 mM, phosphate at a concentration of less than 5 mM; and a pH of 6, wherein less than 5% of the ASA protein exists in aggregated form.
17. The method of claim 16 , 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.
18. The method of claim 16 , wherein less than 1% of the arylsulfatase A (ASA) protein exists in aggregated form.
19. The method of claim 16 , wherein the ASA protein is present at a concentration of at least 10 mg/ml.
20. The method of claim 16 , wherein the ASA protein comprises the amino acid sequence of SEQ ID NO:1.
21. The method of claim 16 , the ASA protein is produced from a human cell line or from CHO cells.
22. The method of claim 16 , wherein the NaCl is present at a concentration of approximately 154 mM.
23. The method of claim 16 , 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.