Methods and compositions for CNS delivery of arylsulfatase A
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 an arylsulfatase A (ASA) protein, salt, and a polysorbate surfactant for the treatment of Metachromatic Leukodystrophy Disease.
1. 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 at or greater than 25 mg/mL and at a dose amount of at least 80 mg/kg brain weight, wherein the formulation comprises no greater than 20 mM of phosphate.
2. The method of claim 1 , wherein the ASA protein is present at a concentration of at least about 30 mg/mL.
3. The method of claim 1 , wherein the ASA protein is present at a concentration of at least about 45 mg/mL.
4. The method of claim 1 , wherein the phosphate is present at a concentration no greater than 10 mM.
5. The method of 1 , wherein the phosphate is present at a concentration no greater than 5 mM.
6. The method of claim 1 , wherein the formulation further comprises salt.
7. The method of claim 6 , wherein the salt is NaCl.
8. The method of claim 1 , wherein the ASA protein comprises an amino acid sequence of SEQ ID NO:1.
9. The method of claim 1 , wherein the ASA protein is produced from a human cell line.
10. The method of claim 1 , wherein the ASA protein is produced from CHO cells.
11. The method of claim 1 , wherein the formulation further comprises a polysorbate surfactant is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 and combination thereof.
12. The method of claim 11 , wherein the wherein the polysorbate surfactant is polysorbate 20 present at a concentration ranging from approximately 0-0.2%.
13. The method of claim 1 , wherein the formulation is a liquid formulation.
14. The method of claim 1 , wherein the formulation is formulated as lyophilized dry powder.
15. The method of claim 1 , wherein the formulation further comprises a stabilizing agent selected from the group consisting of sucrose, glucose, mannitol, sorbitol, PEG 4000, histidine, arginine, lysine, phospholipids and combination thereof.
16. The method of claim 1 , wherein the formulation comprises NaCl at a concentration of approximately 154 mM, polysorbate 20 at a concentration of approximately 0.005%, and a pH of approximately 6.
17. The method of claim 1 , wherein the formulation is administered in a volume of less than 3 mL.
18. The method of claim 1 , wherein formulation is administered at a dose amount is of at least 90 mg/kg brain weight.
19. The method of claim 1 , wherein formulation is administered intrathecally at a total dose amount of at least 100 mg per injection.