Long‐term complications of glycogen storage disease type Ia in the canine model treated with gene replacement therapy

Brooks, Elizabeth D.; Landau, Dustin J.; Everitt, Jeffrey I.; Brown, T. T.; Grady, Kylie M.; Waskowicz, Lauren R; Bass, Cameron R.; D’Angelo, John; Asfaw, Yohannes G.; Williams, Kyha D.; Kishnani, Priya S.; Koeberl, Dwight D.

doi:10.1007/s10545-018-0223-y

Cited by 23 publications

(31 citation statements)

References 64 publications

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“…The GSD Ia canine model provides an outbred genetic model for the study of complications of GSD Ia (34). Three age-matched, male GSD Ia dogs were sustained by adeno-associated virus (AAV) vector-mediated gene therapy as described (35), which partially reversed biochemical abnormalities without preventing the long-term risk for HCA and HCC (36). Ultrasound examination following 1.2, 2.4 and 3.6 months of bezafibrate treatment revealed a more homogenous appearance of the liver after treatment, in comparison with baseline ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The animal models of GSD Ia require gene therapy to promote long-term survival, including both the homozygous G6pc−/− mouse or naturally occurring canine models (40). While G6pc−/− mice were used to evaluate the short-term benefits of bezafibrate, we employed the canine model for GSD Ia to study longterm effects of GSD Ia, including the known occurrence of HCA and HCC (36). Of note, gene therapy cannot prevent these tumors from developing because of the transient nature of AAV vectormediated gene therapy (41).…”

Section: Discussionmentioning

confidence: 99%

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Bezafibrate induces autophagy and improves hepatic lipid metabolism in glycogen storage disease type Ia

Waskowicz

Zhou

Landau

et al. 2018

Human Molecular Genetics

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Glucose-6-phosphatase α (G6Pase) deficiency, also known as von Gierke’s Disease or Glycogen storage disease type Ia (GSD Ia), is characterized by decreased ability of the liver to convert glucose-6-phosphate to glucose leading to glycogen accumulation and hepatosteatosis. Long-term complications of GSD Ia include hepatic adenomas and carcinomas, in association with the suppression of autophagy in the liver. The G6pc−/− mouse and canine models for GSD Ia were treated with the pan-peroxisomal proliferator-activated receptor agonist, bezafibrate, to determine the drug’s effect on liver metabolism and function. Hepatic glycogen and triglyceride concentrations were measured and western blotting was performed to investigate pathways affected by the treatment. Bezafibrate decreased liver triglyceride and glycogen concentrations and partially reversed the autophagy defect previously demonstrated in GSD Ia models. Changes in medium-chain acyl-CoA dehydrogenase expression and acylcarnintine flux suggested that fatty acid oxidation was increased and fatty acid synthase expression associated with lipogenesis was decreased in G6pc−/− mice treated with bezafibrate. In summary, bezafibrate induced autophagy in the liver while increasing fatty acid oxidation and decreasing lipogenesis in G6pc−/− mice. It represents a potential therapy for glycogen overload and hepatosteatosis associated with GSD Ia, with beneficial effects that have implications for non-alcoholic fatty liver disease.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Bezafibrate induces autophagy and improves hepatic lipid metabolism in glycogen storage disease type Ia

Waskowicz

Zhou

Landau

et al. 2018

Human Molecular Genetics

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“…Accumulated glycogen was remarkably decreased in the liver of dogs with GSD Ia, in association with decreased hepatic lipids, following administration of an AAV serotype 2 vector cross-packaged as AAV serotype 8 (AAV2/8-G6Pase), and efficacy was maintained for 1 year 15 . We recently described five GSD Ia dogs treated with AAV-G6Pase therapy that survived up to 8 years; however, four of these dogs had hepatocellular tumors, indicating some loss of therapeutic efficacy 16 …”

Section: Introductionmentioning

confidence: 99%

Pathogenesis of Hepatic Tumors following Gene Therapy in Murine and Canine Models of Glycogen Storage Disease

Kang

Gjorgjieva

Smith

et al. 2019

Molecular Therapy - Methods & Clinical Development

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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.

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“…Our group recently published a very similar gene therapy study, but the GSD Ia dogs were maintained on a more typical diet of only three feedings per day (Brooks et al 2018). However, 4/5 AAV vector-treated dogs developed hepatocellular adenomas and carcinoma and 3/5 developed chronic kidney disease.…”

mentioning

confidence: 99%

“…The kidney sparing in Lee et al can be attributed to intensive dietary therapy (Lee et al 2018). Brooks et al reported tubule-interstitial lesions and glomerular changes in the older GSD Ia dog cohort treated with AAV vectors (Brooks et al 2018). …”

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confidence: 99%

Letter to the Editors: Concerning “Long‐term safety and efficacy of AAV gene therapy in the canine model of glycogen storage disease type Ia” by Lee et al.

Brooks

Kishnani

Koeberl

2018

J of Inher Metab Disea

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Long‐term complications of glycogen storage disease type Ia in the canine model treated with gene replacement therapy

Abstract: Here, we show that the canine GSD Ia model demonstrates similar long-term complications as GSD Ia patients in spite of gene replacement therapy. Further development of gene therapy is needed to develop a more effective treatment to prevent long-term complications of GSD Ia.

Cited by 23 publications

References 64 publications

Bezafibrate induces autophagy and improves hepatic lipid metabolism in glycogen storage disease type Ia

Bezafibrate induces autophagy and improves hepatic lipid metabolism in glycogen storage disease type Ia

Pathogenesis of Hepatic Tumors following Gene Therapy in Murine and Canine Models of Glycogen Storage Disease

Letter to the Editors: Concerning “Long‐term safety and efficacy of AAV gene therapy in the canine model of glycogen storage disease type Ia” by Lee et al.

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