Methods for the treatment of danon disease and other disorders of autophagy

Abstract

This disclosure provides gene therapy vectors comprising a polynucleotide encoding one or more isoforms of lysosome-associated membrane protein 2 (LAMP-2), and methods of using such gene therapy vectors for the treatment of Danon disease and other autophagy disorders.

What is claimed is: 
     
         1 . A gene therapy vector comprising an expression cassette comprising a polynucleotide encoding one or more isoforms of lysosome-associated membrane protein 2 (LAMP-2). 
     
     
         2 . The gene therapy vector of  claim 1 , wherein the vector is a viral vector from a virus selected from the group consisting of adenovirus, retrovirus, lentivirus, herpesvirus, and adeno-associated virus (AAV). 
     
     
         3 . The gene therapy vector of  claim 2 , wherein the vector is from one or more of adeno-associated virus (AAV) serotypes 1-11, or any subgroups thereof. 
     
     
         4 . The gene therapy vector of  claim 2 , wherein the viral vector is encapsulated in an anionic liposome. 
     
     
         5 . The gene therapy vector of  claim 1 , wherein the vector is a non-viral vector selected from the group consisting of naked DNA, a cationic liposome complex, a cationic polymer complex, a cationic liposome-polymer complex, and an exosome. 
     
     
         6 . The gene therapy vector of  claim 1 , wherein the expression cassette comprises operably linked in the 5′ to 3′ direction, a first inverse terminal repeat, an enhancer/promoter region, the polynucleotide encoding one or more isoforms of LAMP-2, a 3′ untranslated region including a polyadenylation signal, and a second inverse terminal repeat. 
     
     
         7 . The gene therapy vector of  claim 6 , wherein the promoter is selected from the group consisting of cytomegalovirus (CMV) promoter and CAG promoter. 
     
     
         8 . The gene therapy vector of  claim 1 , wherein the polynucleotide comprises DNA or cDNA. 
     
     
         9 . The gene therapy vector of  claim 1 , wherein the polynucleotide encoding one or more isoforms of LAMP-2 comprises one or more human LAMP-2 isoforms. 
     
     
         10 . The gene therapy vector of  claim 1 , wherein the polynucleotide encoding one or more isoforms of LAMP-2 comprises one or more LAMP-2 isoforms selected from the group consisting of LAMP-2A, LAMP-2B, and LAMP-2C. 
     
     
         11 . The gene therapy vector of  claim 1 , wherein the polynucleotide encoding one or more isoforms of LAMP-2 has at least about 90% sequence identity to one or more of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3. 
     
     
         12 . The gene therapy vector of  claim 11 , wherein the polynucleotide encoding one or more isoforms of LAMP-2 comprises one or more of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3. 
     
     
         13 . A method of preventing, mitigating, ameliorating, reducing, inhibiting, eliminating, and/or reversing one or more symptoms of Danon disease or another autophagy disorder in a subject in need thereof, comprising administering to the subject a gene therapy vector of  claim 1 . 
     
     
         14 . A method of preventing, mitigating, ameliorating, reducing, inhibiting, eliminating, and/or reversing one or more symptoms of Danon disease or another autophagy disorder in a subject in need thereof, comprising administering to the subject an adeno-associated virus (AAV) vector comprising an expression cassette comprising a polynucleotide encoding one or more isoforms of lysosome-associated membrane protein 2 (LAMP-2). 
     
     
         15 . The method of  claim 13 , wherein the vector is administered via a route selected from the group consisting of intravenous, intra-arterial, intracardiac, intracoronary, intramyocardial, intrarenal, intraurethral, epidural, and intramuscular. 
     
     
         16 . The method of  claim 13 , wherein the vector is administered multiple times. 
     
     
         17 . The method of  claim 13 , wherein the autophagy disorder is selected from the group consisting of end-stage heart failure, myocardial infarction, drug toxicities, diabetes, end-stage renal failure, and aging. 
     
     
         18 . The method of  claim 13 , wherein the subject is exhibiting symptoms of Danon disease or another autophagy disorder. 
     
     
         19 . The method of  claim 13 , wherein the subject has been identified as having reduced or non-detectable LAMP-2 expression. 
     
     
         20 . The method of  claim 13 , wherein the subject has been identified as having a mutated LAMP-2 gene.