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Abstract

Glycogen storage disease type Ia (GSD Ia) is caused by mutations in the glucose-6-phosphatase (G6Pase) catalytic subunit gene (G6PC). GSD Ia complications include hepatocellular adenomas (HCA) with a risk for hepatocellular carcinoma (HCC) formation. Genome editing with adeno-associated virus (AAV) vectors containing a zinc-finger nuclease (ZFN) and a G6PC donor transgene was evaluated in adult mice with GSD Ia. Although mouse livers expressed G6Pase, HCA and HCC occurred following AAV vector administration. Interestingly, vector genomes were almost undetectable in the tumors but remained relatively high in adjacent liver (p < 0.01). G6Pase activity was decreased in tumors, in comparison with adjacent liver (p < 0.01). Furthermore, AAV-G6Pase vector-treated dogs with GSD Ia developed HCC with lower G6Pase activity (p < 0.01) in comparison with adjacent liver. AAV integration and tumor marker analysis in mice revealed that tumors arose from the underlying disorder, not from vector administration. Similarly to human GSD Ia-related HCA and HCC, mouse and dog tumors did not express elevated α-fetoprotein. Taken together, these results suggest that AAV-mediated gene therapy not only corrects hepatic G6Pase deficiency, but also has potential to suppress HCA and HCC in the GSD Ia liver.

Details

Title
Pathogenesis of Hepatic Tumors following Gene Therapy in Murine and Canine Models of Glycogen Storage Disease
Author
Kang, Hye-Ri 1 ; Gjorgjieva, Monika 2 ; Smith, Stephanie N 3 ; Brooks, Elizabeth D 1 ; Chen, Zelin 4 ; Burgess, Shawn M 4 ; Chandler, Randy J 3 ; Waskowicz, Lauren R 1 ; Grady, Kylie M 1 ; Li, Songtao 1 ; Mithieux, Gilles 2 ; Venditti, Charles P 3 ; Rajas, Fabienne 2 ; Koeberl, Dwight D 1 

 Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA 
 U1213, Institut National de la Santé et de la Recherche Médicale, Université Lyon 1, Lyon, France 
 Developmental Genomics Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, Bethesda, MD, USA 
 Organic Acid Research Section, Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA 
Pages
383-391
Section
Original Article
Publication year
2019
Publication date
Dec 13, 2019
Publisher
Elsevier Limited
e-ISSN
23290501
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2324868012
Copyright
©2019. The Authors