Enhancing the effect of therapeutic proteins on the central nervous system

Abstract

The present invention provides a polypeptide therapeutic agent, useful in enzyme replacement therapy, with increased therapeutic benefits for the central nervous system. The invention provides a method of enhancing the effect of a polypeptide or protein on the central nervous system by the attachment of a short acidic amino acid sequence. Specifically the inventors disclose the attachment of a 4-15 acidic amino acid sequence to human β-glucuronidase by construction of a fusion protein. This molecule is useful in the treatment of type VII mucopolysaccharidosis when administered to a patient.

1 . A polypeptide therapeutic agent with increased central nervous system therapeutic activity comprised of a) a physiologically active protein with therapeutic benefits for the central nervous system, and b) a short peptide which consisting of 4-15 acidic amino acids attached to the physiology active protein via the N-terminus thereof.  
   
   
       2 . A polypeptide therapeutic agent as in  claim 1  wherein said physiologically active protein is an enzyme.  
   
   
       3 . A polypeptide therapeutic agent as in  claim 1  wherein said physiologically active protein is an enzyme known to be therapeutic in treatment of lysosomal storage disease.  
   
   
       4 . A polypeptide therapeutic agent as in  claim 1  wherein said physiologically active protein is human β-glucuronidase.  
   
   
       5 . A polypeptide therapeutic agent as in  claim 1  wherein attaching said acid amino acid sequence of 4-15 amino acids to the N terminus of said polypeptide increases clearance time in the blood.  
   
   
       6 . A polypeptide therapeutic agent as in  claim 1  whereby attached comprises produced a fusion protein through genetic engineering.  
   
   
       7 . A polypeptide therapeutic agent as in  claim 1  whereby attached comprises chemically linking at least two molecules.  
   
   
       8 . A polypeptide therapeutic agent as in  claim 1  whereby attached is via a linker peptide.  
   
   
       9 . A method of increasing therapeutic benefits of a physiologically active protein on the central nervous system wherein the method comprises, a) a physiologically active protein with therapeutic benefits for the central nervous system, and b) a short peptide consisting of 4-15 acidic amino acids, which is c) attached to said physiology active protein via the N-terminus thereof.  
   
   
       10 . A method of increasing therapeutic benefits as in  claim 9  whereby said physiologically active protein is an enzyme.  
   
   
       11 . A method of increasing therapeutic effects as in  claim 9  whereby said physiologically active protein is an enzyme known to be therapeutic in treatment of lysosomal storage disease.  
   
   
       12 . A method of increasing therapeutic effects as in  claim 9  whereby said physiologically active protein is human β-glucuronidase.  
   
   
       13 . A method of increasing therapeutic effects as in  claim 9  whereby attaching said acid amino acid sequence of 4-15 amino acids to the N terminus of said polypeptide increases clearance time in the blood.  
   
   
       14 . A method of increasing therapeutic effects as in  claim 9  whereby attaching comprises a fusion protein produced through genetic engineering.  
   
   
       15 . A method of increasing therapeutic effects as in  claim 9  whereby attaching comprises chemically linking at least two molecules.  
   
   
       16 . A method of increasing therapeutic effects as in  claim 9  whereby attaching is via a linker peptide.  
   
   
       17 . A method of treating a patient with a central nervous system disease by administering an effective amount of a physiologically active protein with therapeutic benefits for the central nervous system, and b) a short peptide which consists of 4-15 acidic amino acids, which is c) attached to the physiology active protein on the N-terminus thereof.  
   
   
       18 . A method as in  claim 17  whereby said physiologically active protein is human β-glucuronidase.  
   
   
       19 . A method as in  claim 17  whereby said central nervous system disease is a lysosomal storage disease.  
   
   
       20 . A method as in  claim 17  whereby said central nervous system disease is type VII mucopolysaccharidosis.  
   
   
       21 . A method as in  claim 17  whereby said physiologically active protein with said short peptide attached further comprises increased clearance time in the blood.