A Novel Gene Therapy Approach for GSD III Using an AAV Vector Encoding a Bacterial Glycogen Debranching Enzyme.

Journal Article (Journal Article)

Glycogen storage disease type III (GSD III) is an inherited disorder caused by a deficiency of glycogen debranching enzyme (GDE), which results in the accumulation of abnormal glycogen (limit dextrin) in the cytoplasm of liver, heart, and skeletal muscle cells. Currently, there is no curative treatment for this disease. Gene therapy with adeno-associated virus (AAV) provides an optimal treatment approach for monogenic diseases like GSD III. However, the 4.6 kb human GDE cDNA is too large to be packaged into a single AAV vector due to its small carrying capacity. To overcome this limitation, we tested a new gene therapy approach in GSD IIIa mice using an AAV vector ubiquitously expressing a smaller bacterial GDE, Pullulanase, whose cDNA is 2.2 kb. Intravenous injection of the AAV vector (AAV9-CB-Pull) into 2-week-old GSD IIIa mice blocked glycogen accumulation in both cardiac and skeletal muscles, but not in the liver, accompanied by the improvement of muscle functions. Subsequent treatment with a liver-restricted AAV vector (AAV8-LSP-Pull) reduced liver glycogen content by 75% and reversed hepatic fibrosis while maintaining the effect of AAV9-CB-Pull treatment on heart and skeletal muscle. Our results suggest that AAV-mediated gene therapy with Pullulanase is a possible treatment for GSD III.

Full Text

Duke Authors

Cited Authors

  • Lim, J-A; Choi, SJ; Gao, F; Kishnani, PS; Sun, B

Published Date

  • September 11, 2020

Published In

Volume / Issue

  • 18 /

Start / End Page

  • 240 - 249

PubMed ID

  • 32637453

Pubmed Central ID

  • PMC7327847

International Standard Serial Number (ISSN)

  • 2329-0501

Digital Object Identifier (DOI)

  • 10.1016/j.omtm.2020.05.034


  • eng

Conference Location

  • United States