Methods and compositions for treatment of glycogen storage diseases and glycogen metabolism disorders
The present disclosure provides for compositions comprising a chimeric polypeptide comprising a polypeptide effective for treating glycogen storage disease and an internalizing moiety that promotes delivery into cells. In certain embodiments, the polypeptide effective for treating glycogen storage disease is an acid alpha-glucosidase (GAA), a laforin, an amyloglucosidase (AGL), a malin, or an alpha amylase. The present disclosure also provides for methods for decreasing glycogen accumulation in cells or for treating glycogen storage diseases, including Forbes-Cori Disease, Andersen Disease, von Gierke Disease, Pompe Disease, and Lafora Disease, comprising administering the chimeric polypeptide disclosed herein.
1. A composition comprising: (i) an alpha-amylase polypeptide, and (ii) an internalizing moiety, wherein the internalizing moiety promotes delivery of the composition into cells via ENT2, and wherein the alpha-amylase polypeptide is interconnected with the internalizing moiety.
2. The composition of claim 1 , wherein the alpha-amylase polypeptide is a pancreatic alpha-amylase.
3. The composition of claim 1 , wherein the alpha-amylase polypeptide is a salivary alpha-amylase.
4. The composition of claim 1 , wherein the alpha-amylase polypeptide comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 44 or 45, or a biologically active fragment thereof.
5. The composition of claim 1 , wherein the alpha-amylase polypeptide comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 44 or 45, or a biologically active fragment thereof.
6. The composition of claim 1 , wherein the composition has alpha-1,4-glucosidic bonds hydro lytic activity.
7. The composition of claim 1 , wherein the alpha-amylase polypeptide is chemically conjugated to the internalizing moiety.
8. The composition of claim 1 , wherein the composition comprises a fusion protein comprising the alpha-amylase polypeptide and the internalizing moiety.
9. The composition of claim 8 , wherein the fusion protein comprises a linker.
10. The composition of claim 9 , wherein the linker conjugates or joins the alpha-amylase polypeptide to the internalizing moiety.
11. The composition of claim 9 , wherein the linker is a cleavable linker.
12. The composition of claim 1 , wherein the composition does not include a linker interconnecting the alpha-amylase polypeptide to the internalizing moiety.
13. The composition of claim 1 , wherein the internalizing moiety promotes delivery of said composition into one or more of muscle cells, hepatocytes and fibroblasts.
14. The composition of claim 1 , wherein the internalizing moiety promotes delivery of said composition into neuronal cells.
15. The composition of claim 1 , wherein the internalizing moiety comprises an antibody or antigen binding fragment.
16. The composition of claim 1 , wherein the internalizing moiety comprises a homing peptide.
17. A method of treating a glycogen storage disease in a subject in need thereof, comprising administering a composition comprising: (i) an alpha-amylase polypeptide, and (ii) an internalizing moiety that promotes delivery into cells, wherein the internalizing moiety can transit cellular membranes via an equilibrative nucleoside transporter 2 (ENT2) transporter, and wherein the alpha-amylase polypeptide is interconnected with the internalizing moiety.
18. The method of claim 17 , wherein the subject has a mutation in the EPM2A gene.
19. The method of claim 17 , wherein the subject has a mutation in the EPM2B gene.
20. The method of claim 17 , wherein the glycogen storage disease is Lafora Disease.
21. A method of decreasing glycogen accumulation in cytoplasm of cells of a subject having a glycogen storage disease, comprising administering to the subject a composition comprising (i) an alpha-amylase polypeptide, and (ii) an internalizing moiety that promotes transport into cytoplasm of cells via an equilibrative nucleoside transporter 2 (ENT2) transporter, wherein the administered composition contacts neuronal cells, and wherein the alpha-amylase polypeptide is interconnected with the internalizing moiety.
22. The method of claim 21 , wherein the glycogen storage disease is Lafora Disease.