Stable formulations for cns delivery of arylsulfatase a

Abstract

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.