Methods and compositions for increasing n-acetylglucosaminidase activity in the cns

Abstract

Provided herein are methods and compositions for treating a subject suffering from an enzyme deficiency in the central nervous system (CNS). The bifunctional fusion antibody provided herein comprise an antibody to an endogenous blood brain barrier (BBB) receptor and an enzyme deficient in mucopolysaccharidosis IIIB (MPS-IIIB). The fusion antibodies provided herein comprise alpha-N-acetylgulcosaminidase (NAGLU). The methods of treating an enzyme deficiency in the CNS comprise systemic administration of a fusion antibody provided herein.

What is claimed: 
     
         1 . A method for treating an alpha-N-acetylglucosaminidase (NAGLU) deficiency in the central nervous system of a subject in need thereof, comprising:
 systemically administering to the subject a pharmaceutical composition comprising:
 a therapeutically effective dose of a fusion antibody having NAGLU activity,
 wherein the fusion antibody comprises:
 (a) a fusion protein comprising an amino acid sequence of an immunoglobulin heavy chain and an amino acid sequence of a NAGLU, and 
 (b) an immunoglobulin light chain; 
 
 wherein the fusion antibody crosses the blood brain barrier (BBB), and 
 
 a pharmaceutical acceptable excipient. 
   
     
     
         2 . The method of  claim 1 , wherein the amino acid sequence of the NAGLU is covalently linked to an amino terminus of the amino acid sequence of the immunoglobulin heavy chain. 
     
     
         3 . The method of  claim 1 , wherein the amino acid sequence of the NAGLU is covalently linked to a carboxy terminus of the amino acid sequence of the immunoglobulin heavy chain. 
     
     
         4 . The method of  claim 1 , wherein the fusion antibody catalyzes hydrolysis of terminal N-acetyl-D-glucosamine residues in N-acetyl-alpha-D-glucosaminides of heparan sulfate. 
     
     
         5 . The method of  claim 1 , wherein the NAGLU retains at least 20% of its activity compared to its activity as a separate entity. 
     
     
         6 . The method of  claim 1 , wherein the NAGLU and the immunoglobulin each retains at least 20% of its activity compared to its activity as a separate entity. 
     
     
         7 . The method of  claim 1 , wherein at least about 200 ug of NAGLU enzyme are delivered to the brain, normalized per 50 kg body weight. 
     
     
         8 . The method of  claim 1 , wherein the therapeutically effective dose comprises at least about 10,000 units/Kg of body weight. 
     
     
         9 . The method of  claim 1 , wherein the NAGLU specific activity of the fusion antibody is at least 10,000 units/mg. 
     
     
         10 . The method of  claim 1 , wherein the fusion antibody crosses the BBB via an endogenous BBB receptor selected from the group consisting of the insulin receptor, transferrin receptor, leptin receptor, lipoprotein receptor, and the insulin-like growth factor (IGF) receptor. 
     
     
         11 . The method of  claim 1 , wherein the NAGLU deficiency in the central system is mucopolysaccharidosis Type TIM (MPS-IIIB) or Sanfilippo syndrome type B.