Methods of treating lysosomal storage related diseases by gene therapy

Abstract

Isolated nucleic acid-based vectors and lentivirus vectors, and methods of using those vectors to inhibit or prevent metabolic disorders in a mammal, are provided.

1 . A method to prevent, inhibit or treat a disorder characterized by the absence or reduced levels of a lysosomal enzyme in a mammal, comprising: administering to a vascular compartment of a mammal having or at risk of the disorder, an effective amount of a recombinant lentivirus comprising a nucleic acid segment encoding the enzyme. 
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1  wherein the protein is alpha-L-iduronidase, iduronate-2-sulfatase, heparan sulfate sulfatase, N-acetyl-alpha-D-glucosaminidase, beta-hexosamine, alpha-galactosidase, beta-galactosidase, beta-glucuronidase or glucocerebrosidase. 
     
     
         4 . The method of  claim 1  wherein the recombinant lentivirus comprises a heterologous promoter operably linked to the nucleic acid segment. 
     
     
         5 . The method of  claim 1  wherein vascular compartment is a vein, artery, bone marrow cavity, heart, spleen, umbilical cord vessel or placenta. 
     
     
         6 . The method of  claim 1  wherein the mammal is a human. 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 1  wherein the recombinant lentivirus is a pseudotyped virus. 
     
     
         9 . The method of  claim 1  wherein the lentivirus is a human immunodeficiency virus-1 (HIV-1). 
     
     
         10 . The method of  claim 1  wherein the disorder is a mucopolysaccharide disorder. 
     
     
         11 . The method of  claim 10  wherein the disorder is a mucopolysaccharidosis type I disorder. 
     
     
         12 . The method of  claim 10  wherein the disorder is a mucopolysaccharidosis type VII disorder. 
     
     
         13 . (canceled) 
     
     
         14 . The recombinant virus of  claim 18  wherein the enzyme is alpha-L-iduronidase, beta-hexosamine, alpha-galactosidase, beta-galactosidase, beta-glucuronidase or glucocerebrosidase. 
     
     
         15 . The recombinant virus of  claim 18  wherein the lentivirus is HIV-1. 
     
     
         16 . The recombinant virus of  claim 18  wherein the U3 of the 5′LTR is modified by substantially replacing the U3 of the 5′LTR with a heterologous promoter. 
     
     
         17 . The recombinant virus of  claim 18  which further comprises a promoter operably linked to the nucleic acid segment. 
     
     
         18 . Recombinant virus comprising a lentivirus vector comprising a 5N LTR and a 3N LTR and a nucleic acid segment encoding a lysosomal enzyme, wherein the U3 region of at least one LTR is optionally modified. 
     
     
         19 . The recombinant virus of  claim 18  which is a pseudotyped virus. 
     
     
         20 . A method for providing a biologically active lysosomal enzyme to a cell of a mammal, comprising: contacting the cell with an effective amount of a recombinant lentivirus comprising a nucleic acid segment encoding the enzyme. 
     
     
         21 . The method of  claim 1  wherein the mammal is a newborn. 
     
     
         22 . The method of  claim 1  wherein the lentivirus is intravenously administered.