Intraventricular enzyme delivery for lysosomal storage diseases

Abstract

Lysosomal storage diseases can be successfully treated using intraventricular delivery of the enzyme which is etiologically deficient in the disease. The administration can be performed slowly to achieve maximum effect. Surprisingly, effects are seen on both sides of the blood-brain barrier, making this an ideal delivery means for lysosomal storage diseases which affect both brain and visceral organs.

1 - 27 . (canceled) 
     
     
         28 : A method of treating a patient with a lysosomal storage disease which is caused by an enzyme deficiency wherein the enzyme deficiency leads to an accumulation of the enzyme's substrate, the method comprising:
 administering the enzyme to the patient via intraventricular delivery to the brain wherein administering a single dose of the enzyme consumes two hours, and wherein administering the enzyme leads to a reduction in the level of the substrate in the brain and in one or more of the visceral organs.   
     
     
         29 - 41 . (canceled) 
     
     
         42 : The method of  claim 28 , wherein the enzyme is administered to the lateral ventricles and/or to the fourth ventricle of the brain. 
     
     
         43 : The method of  claim 28 , wherein the enzyme is administered to one or both of the lateral ventricles of the brain. 
     
     
         44 : The method of  claim 28 , wherein the amount of enzyme administered is sufficient to reduce sphingomyelin levels in the brain at least 10% in the patient. 
     
     
         45 : The method of  claim 28 , wherein the amount of enzyme administered is sufficient to reduce sphingomyelin levels in the liver, lungs, spleen, or kidney of the patient. 
     
     
         46 : The method of  claim 28 , wherein the lysosomal storage disease involves both CNS and visceral pathologies. 
     
     
         47 : The method of  claim 28 , wherein the enzyme is an acid sphingomyelinase, and wherein the acid sphingomyelinase shares at least 95% amino acid sequence identity with an acid sphingomyelinase as shown in SEQ ID NO: 1. 
     
     
         48 : The method of  claim 28 , wherein:
 (i) the lysosomal storage disease is Niemann-Pick A or B disease and the enzyme is sphingomyelinase;   (ii) the lysosomal storage disease is Gaucher disease and the enzyme is an glucocerebrosidase;   (iii) the lysosomal storage disease is Pompe disease and the enzyme is an acid alpha glucosidase;   (iv) the lysosomal storage disease is Mucopolysaccharidosis I syndrome and the enzyme is alpha-L-iduronidase;   (v) the lysosomal storage disease is Mucopolysaccharidosis II syndrome and the enzyme is iduronate-2-sulfatase; or,   (vi) the lysosomal storage disease is classic late infantile Batten disease (CLN2) and the enzyme is tripeptidyl peptidase.   
     
     
         49 : The method of  claim 28 , wherein the enzyme is administered using a pump and/or an indwelling catheter. 
     
     
         50 : The method of  claim 28 , wherein the step of administering comprises a plurality of infusions of the enzyme. 
     
     
         51 : A method of treating a patient with a lysosomal storage disease which is caused by an enzyme deficiency wherein the enzyme deficiency leads to an accumulation of the enzyme's substrate, the method comprising:
 a) administering the enzyme to the patient via intraventricular delivery to the brain,   b) determining the reaccumulation of sphingomyelin in the brain and/or in one or more of the visceral organs,   wherein administration of the enzyme leads to a reduction in the level of the substrate in the brain and in one or more of the visceral organs.   
     
     
         52 : The method of  claim 51 , wherein the enzyme is administered to the lateral ventricles and/or to the fourth ventricle of the brain. 
     
     
         53 : The method of  claim 51 , wherein the enzyme is administered to one or both of the lateral ventricles of the brain. 
     
     
         54 : The method of  claim 51 , wherein the amount of enzyme administered is sufficient to reduce sphingomyelin levels in the brain at least 10% in the patient. 
     
     
         55 : The method of  claim 51 , wherein the amount of enzyme administered is sufficient to reduce sphingomyelin levels in the liver, lungs, spleen, or kidney of the patient. 
     
     
         56 : The method of  claim 51 , wherein the lysosomal storage disease involves both CNS and visceral pathologies. 
     
     
         57 : The method of  claim 51 , wherein the enzyme is an acid sphingomyelinase, and wherein the acid sphingomyelinase shares at least 95% amino acid sequence identity with an acid sphingomyelinase as shown in SEQ ID NO: 1. 
     
     
         58 : The method of  claim 51 , wherein:
 (i) the lysosomal storage disease is Niemann-Pick A or B disease and the enzyme is sphingomyelinase;   (ii) the lysosomal storage disease is Gaucher disease and the enzyme is an glucocerebrosidase;   (iii) the lysosomal storage disease is Pompe disease and the enzyme is an acid alpha glucosidase;   (iv) the lysosomal storage disease is Mucopolysaccharidosis I syndrome and the enzyme is alpha-L-iduronidase;   (v) the lysosomal storage disease is Mucopolysaccharidosis II syndrome and the enzyme is iduronate-2-sulfatase; or,   (vi) the lysosomal storage disease is classic late infantile Batten disease (CLN2) and the enzyme is tripeptidyl peptidase.   
     
     
         59 : The method of  claim 51 , wherein the enzyme is administered using a pump and/or an indwelling catheter. 
     
     
         60 : The method of  claim 51 , wherein the step of administering comprises a plurality of infusions of the enzyme.