Vlp for the treatment of a lysosomal storage disease

Abstract

The invention relates to virus like particles (VLP) associated with a lysosomal enzyme or an expression vector encoding a lysosomal enzyme which are used in a method for the treatment of a lysosomal storage disease. The invention also relates to a pharmaceutical composition for use in a method for the treatment of a lysosomal storage disease, to an expression vector encoding a lysosomal enzyme and to a method of associating a VLP with an expression vector encoding a lysosomal enzyme.

1 . VLP incorporating a lysosomal enzyme or incorporating an expression vector encoding a lysosomal enzyme for use in a method for the treatment of Metachromatic Leukodystrophy Disease (MLD) in a subject, wherein the VLP is derived from JCV. 
     
     
         2 . The VLP for use according to  claim 1 , wherein the VLP does not comprise viral genetic material and the expression vector does not encode viral proteins. 
     
     
         3 . The VLP for use according to  claim 1  or  2 , wherein the subject is an animal or a human being, preferably a human being. 
     
     
         4 . The VLP for use according to any of the preceding claims, wherein the subject has a neurologic deficit. 
     
     
         5 . The VLP for use according to any of the preceding claims, wherein the lysosomal enzyme is a human enzyme. 
     
     
         6 . The VLP for use according to any of the preceding claims, wherein the lysosomal enzyme is arylsulfatase A. 
     
     
         7 . The VLP for use according to any of the preceding claims, wherein the lysosomal enzyme comprises an amino acid sequence which is at least 80%, more preferably at least 90% identical to the amino acid sequence according to SEQ ID NO: 1 over its entire length, most preferably has the amino acid sequence of SEQ ID NO: 1. 
     
     
         8 . The VLP for use according to any of the preceding claims, wherein the expression vector has a size of less than 7 kb, preferably less than 6 kb. 
     
     
         9 . The VLP for use according to any of the preceding claims, wherein the expression vector has a promoter selected from the group comprising CMV and CAG. 
     
     
         10 . The VLP for use according to any of the preceding claims, wherein the lysosomal enzyme comprises a nucleotide sequence which is at least 70%, more preferably at least 80%, more preferably at least 90% identical to the nucleotide sequence of SEQ ID NO: 2 over its entire length, preferably is the nucleotide sequence of SEQ ID NO: 2. 
     
     
         11 . The VLP for use according to any of the preceding claims, wherein the VLP crosses the blood-brain barrier, preferably the physiologically intact blood-brain barrier, to enter the CNS together with the lysosomal enzyme or the expression vector. 
     
     
         12 . The VLP according to  claim 11 , wherein the lysosomal enzyme or the expression vector enters astrocytes, oligodendrocytes, microglia or neurons, preferably oligodendrocytes. 
     
     
         13 . The VLP for use according to any of the preceding claims, wherein the VLP is administered orally or parenterally, preferably intravenously. 
     
     
         14 . The VLP for use according to any of the preceding claims, wherein a target cell is contacted with an effective amount of the lysosomal enzyme. 
     
     
         15 . The VLP for use according to any of the preceding claims, wherein the lysosomal enzyme has a therapeutically effective enzyme activity for at least 10 days, preferably for at least 20 days, more preferably for at least 30 days. 
     
     
         16 . The VLP for use according to any of the preceding claims, wherein the VLP is composed of VP1 proteins of JC virus. 
     
     
         17 . The VLP according to  claim 16 , wherein the VP1 protein comprises an amino acid sequence which is at least 80% identical to the amino acid sequence according to SEQ ID NO: 3 over its entire length, preferably at least 90% identical. 
     
     
         18 . Pharmaceutical composition for use in a method for the treatment of a lysosomal storage disease in a subject, wherein the pharmaceutical composition comprises the VLP according to any of  claims 1  to  17  and a pharmaceutically acceptable carrier, and/or excipient. 
     
     
         19 . Expression vector having a coding region encoding a lysosomal enzyme, preferably human arylsulfatase A, a promoter selected from the group comprising CAG and CMV, preferably being CAG, and having a size of less than 7 kb, preferably less than 6 kb. 
     
     
         20 . The expression vector according to  claim 19 , wherein the lysosomal enzyme comprises a nucleotide sequence which is at least 70%, more preferably at least 80%, more preferably at least 90% identical to the nucleotide sequence of SEQ ID NO: 2 over its entire length, preferably is the nucleotide sequence of SEQ ID NO: 2. 
     
     
         21 . Method of incorporating a lysosomal enzyme, preferably human arylsulfatase A, or incorporating an expression vector encoding a lysosomal enzyme, preferably human arylsulfatase A, into a VLP, wherein the method comprises the following steps:
 a) providing a composition comprising VP1 proteins,   b) exposing the VP1 proteins of the composition of a) to conditions Inducing the VP1 to assemble into VLP,   c) exposing the VLP of the composition of b) to conditions disassembling the VLP into pentamers,   d) exposing the pentamers of the composition of c) to conditions inducing the pentamers to reassemble into VLP   e) exposing the VLP of the composition of d) to conditions disassembling the VLP into pentamers,   f) exposing the pentamers of the composition of e) to the lysosomal enzyme or the expression vector to conditions inducing the pentamers to assemble into a VLP associated with the lysosomal enzyme or the expression vector.   
     
     
         22 . VLP obtainable by the method according to  claim 21 . 
     
     
         23 . A drug delivery system obtainable by the method according to  claim 21 . 
     
     
         24 . The VLP for use according to any of  claims 1  to  17  as a drug delivery system. 
     
     
         25 . The VLP for use according to  claim 24 , wherein the method of treatment of MLD does not comprise a step of increasing the permeability of a BBB of the subject to be treated. 
     
     
         26 . Method of treating MLD with VLP incorporating a lysosomal enzyme or an expression vector encoding a lysosomal enzyme, wherein the VLP is derived from JCV. 
     
     
         27 . VLP incorporating a lysosomal enzyme or an expression vector encoding a lysosomal enzyme for use in delivering the lysosomal enzyme or the expression vector encoding the lysosomal enzyme to a target, wherein the target is the CNS. 
     
     
         28 . The VLP for use according to  claim 27 , wherein the lysosomal enzyme or the expression vector encoding the lysosomal enzyme is delivered to a target cell in the CNS, in particular an astrocyte, an oligodendrocyte, a neuron and/or microglia. 
     
     
         29 . The VLP for use according to  claim 28 , wherein the lysosomal enzyme is transiently expressed in the target cell. 
     
     
         30 . VLP incorporating a lysosomal enzyme or an expression vector encoding a lysosomal enzyme for use in enhancing the lysosomal enzyme activity. 
     
     
         31 . Use of the VLP according to any of  claims 1  to  17  for the manufacture of a medicament for the treatment of MLD. 
     
     
         32 . Use of the drug delivery system according to  claim 23  for the manufacture of a medicament for the treatment of MLD.