Disabling autophagy as a treatment for lysosomal storage diseases

Abstract

Provided herein are methods of treating lysosomal storage disease, for instance Pompe disease, through inhibition of autophagy. Optionally, treatment is administered as an adjunct to enzyme replacement therapy (ERT).

1 . A method of treating a lysosomal storage disorder in a subject, comprising:
 administering a therapeutically effective amount of an agent that inhibits autophagy to a subject with a lysosomal storage disorder, thereby treating the lysosomal storage disorder in the subject.   
     
     
         2 . The method of  claim 1 , wherein the lysosomal storage disorder is Pompe disease. 
     
     
         3 . The method of  claim 1 , wherein the subject is undergoing enzyme replacement therapy (ERT) for the treatment of the lysosomal storage disorder. 
     
     
         4 . The method of  claim 3 , wherein the lysosomal storage disorder is Pompe disease. 
     
     
         5 . The method of  claim 1 , wherein the agent inhibits autophagy in skeletal muscle. 
     
     
         6 . The method of  claim 1 , wherein agent is administered intramuscularly. 
     
     
         7 . The method of  claim 1 , wherein the agent comprises a detectable label. 
     
     
         8 . The method of  claim 1 , wherein the agent is conjugated to a cell-penetrating peptide. 
     
     
         9 . The method of  claim 1 , wherein the administering comprises administering to the subject a therapeutically effective amount of:
 (a) an oligonucleotide comprising at least 15 bases and that hybridizes under high stringency conditions to an mRNA encoding an essential autophagy gene;   (b) a morpholino oligonucleotide comprising at least 15 bases and that hybridizes under high stringency conditions to an mRNA encoding an essential autophagy gene;   (c) an shRNA comprising at least 15 bases and that hybridizes under high stringency conditions to an mRNA encoding an essential autophagy gene;   (d) an agent that decreases expression of an essential autophagy gene;   (e) an agent that inhibits an activity of an essential autophagy gene;   (f) an agent that inhibits activity of class III PI3 kinase; or   (g) a mixture or combination of two or more of a, b, c, d, e, or f.   
     
     
         10 . The method of  claim 9 , wherein the essential autophagy gene is Atg5 or Atg7. 
     
     
         11 . The method of  claim 5 , wherein the oligonucleotide, the morpholino oligonucleotide, the shRNA, the agent that decreases expression of an essential autophagy gene, the agent that inhibits an activity of an essential autophagy gene, or the agent that inhibits activity of class III PI3 kinase, is conjugated to a cell-penetrating peptide. 
     
     
         12 . The method of  claim 5 , wherein the shRNA is expressed from a plasmid. 
     
     
         13 . The method of  claim 5 , wherein the shRNA comprises the sequence set forth as SEQ ID NO: 16. 
     
     
         14 . The method of  claim 5 , wherein the oligonucleotide, morpholino oligonucleotide or shRNA is at least 80%, at least 85%, at least 90%, at least 95% or at least 99% complementary to the mRNA encoding the essential autophagy gene. 
     
     
         15 . The method of  claim 1 , wherein the autophagy inhibitor comprises a morpholino oligonucleotide comprising at least 15 bases and that hybridizes under high stringency conditions to Atg5 or Atg7. 
     
     
         16 . The method of  claim 16 , wherein the shRNA comprises the sequence set forth as SEQ ID NO: 16. 
     
     
         17 . The method of  claim 16 , wherein the subject is undergoing enzyme replacement therapy (ERT) for the treatment of the lysosomal storage disorder, and wherein the lysosomal storage disorder is Pompe disease. 
     
     
         18 . The method of  claim 5 , wherein the lysosomal storage disorder is Pompe disease.