Bezafibrate Enhances AAV Vector-Mediated Genome Editing in Glycogen Storage Disease Type Ia

Kang, Hye-Ri; Waskowicz, Lauren R; Seifts, Andrea M.; Landau, Dustin J.; Young, Sarah P.; Koeberl, Dwight D.

doi:10.1016/j.omtm.2019.02.002

Cited by 7 publications

(5 citation statements)

References 40 publications

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“…Activation of autophagy is critical for energy utilization and clearance of intracellular lipid, which can preferentially hydrolyze intrahepatic lipid droplets to promote mitochondrial fatty acids β ‐oxidation 101 . A number of previous studies have demonstrated the use of drugs to promote hepatic autophagy in the treatment of GSDIa mice, such as VK2809, fenofibrate as well as bezafibrate 69,71,102 . Recently, mediator complex subunit 1 (MED1) has play an important role in regulating hepatic autophagy, β ‐oxidation of fatty acids, and mitochondrial function 103 .…”

Section: Discussion and Future Directionsmentioning

confidence: 99%

“… 101 A number of previous studies have demonstrated the use of drugs to promote hepatic autophagy in the treatment of GSDIa mice, such as VK2809, fenofibrate as well as bezafibrate. 69 , 71 , 102 Recently, mediator complex subunit 1 (MED1) has play an important role in regulating hepatic autophagy, β -oxidation of fatty acids, and mitochondrial function. 103 The effect of MED1 on glycogen storage disease has not been studied and it may be an alternative drug for glycogen storage disease.…”

Section: Discussion and Future Directionsmentioning

confidence: 99%

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Glycogen storage disease type I: Genetic etiology, clinical manifestations, and conventional and gene therapies

Zhong

Gou

Zhao

et al. 2023

Pediatric Discovery

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Glycogen storage disease type I (GSDI) is an inherited metabolic disorder characterized by a deficiency of enzymes or proteins involved in glycogenolysis and gluconeogenesis, resulting in excessive intracellular glycogen accumulation. While GSDI is classified into four different subtypes based on molecular genetic variants, GSDIa accounts for approximately 80%. GSDIa and GSDIb are autosomal recessive disorders caused by deficiencies in glucose‐6‐phosphatase (G6Pase‐α) and glucose‐6‐phosphate‐transporter (G6PT), respectively. For the past 50 years, the care of patients with GSDI has been improved following elaborate dietary managements. GSDI patients currently receive dietary therapies that enable patients to improve hypoglycemia and alleviate early symptomatic signs of the disease. However, dietary therapies have many limitations with a risk of calcium, vitamin D, and iron deficiency and cannot prevent long‐term complications, such as progressive liver and renal failure. With the deepening understanding of the pathogenesis of GSDI and the development of gene therapy technology, there is great progress in the treatment of GSDI. Here, we review the underlying molecular genetics and the current clinical management strategies of GSDI patients with an emphasis on promising experimental gene therapies.

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Section: Discussion and Future Directionsmentioning

confidence: 99%

Section: Discussion and Future Directionsmentioning

confidence: 99%

Glycogen storage disease type I: Genetic etiology, clinical manifestations, and conventional and gene therapies

Zhong

Gou

Zhao

et al. 2023

Pediatric Discovery

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“…154 Intriguingly, the addition of bezafibrate to induce autophagy during genome editing of G6pc À/À mice more effectively corrected the liver abnormalities of GSD Ia, achieving normal G6Pase activity in liver and widespread transduction of hepatocytes. 158 More recently, CRISPR/ Cas9 based genome editing has been used to correct a mutation causing GSD Ia in mice. 159 Instead of inserting a full length transgene, they targeted the most common mutation in GSD Ia patients, G6PC-p.R83C, which represents 32% of all diseased alleles in humans.…”

Section: Preclinical Development Of Gene Therapy and Genome Editing F...mentioning

confidence: 99%

“…An initial genome editing study used a zinc finger nuclease (ZFN) mediated genome editing method, which demonstrated an advantage for genome editing in comparison with gene replacement therapy 154 . Intriguingly, the addition of bezafibrate to induce autophagy during genome editing of G6pc −/− mice more effectively corrected the liver abnormalities of GSD Ia, achieving normal G6Pase activity in liver and widespread transduction of hepatocytes 158 . More recently, CRISPR/Cas9 based genome editing has been used to correct a mutation causing GSD Ia in mice 159 .…”

Section: Preclinical Research In Gsd Gene Therapymentioning

confidence: 99%

Gene therapy for glycogen storage diseases

Koeberl

Koch

Lim

et al. 2023

J of Inher Metab Disea

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Glycogen storage disorders (GSDs) are inherited disorders of metabolism resulting from the deficiency of individual enzymes involved in the synthesis, transport, and degradation of glycogen. This literature review summarizes the development of gene therapy for the GSDs. The abnormal accumulation of glycogen and deficiency of glucose production in GSDs lead to unique symptoms based upon the enzyme step and tissues involved, such as liver and kidney involvement associated with severe hypoglycemia during fasting and the risk of long‐term complications including hepatic adenoma/carcinoma and end stage kidney disease in GSD Ia from glucose‐6‐phosphatase deficiency, and cardiac/skeletal/smooth muscle involvement associated with myopathy +/− cardiomyopathy and the risk for cardiorespiratory failure in Pompe disease. These symptoms are present to a variable degree in animal models for the GSDs, which have been utilized to evaluate new therapies including gene therapy and genome editing. Gene therapy for Pompe disease and GSD Ia has progressed to Phase I and Phase III clinical trials, respectively, and are evaluating the safety and bioactivity of adeno‐associated virus vectors. Clinical research to understand the natural history and progression of the GSDs provides invaluable outcome measures that serve as endpoints to evaluate benefits in clinical trials. While promising, gene therapy and genome editing face challenges with regard to clinical implementation, including immune responses and toxicities that have been revealed during clinical trials of gene therapy that are underway. Gene therapy for the glycogen storage diseases is under development, addressing an unmet need for specific, stable therapy for these conditions.

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“…One example is a recent report showing that bezafibrate not only induced hepatic autophagy but also potentiated rAAV-mediated genome editing in GSD-Ia. 69 Before we establish the safety and efficacy of autophagy modulators in clinical settings, however, tight metabolic control which possibly improves hepatic autophagy in GSD-Ia may be an essential prerequisite for successful gene therapy in GSD-Ia ( Figure 4).…”

Section: Potential Role Of Autophagy In Gene Therapy In Gsd-iamentioning

confidence: 99%

Emerging roles of autophagy in hepatic tumorigenesis and therapeutic strategies in glycogen storage disease type Ia: A review

Cho

Weinstein

Lee

2020

J of Inher Metab Disea

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Glycogen storage disease type Ia (GSD‐Ia) is an inherited metabolic disease caused by a deficiency in glucose‐6‐phosphatase‐α (G6Pase‐α or G6PC) which plays a critical role in blood glucose homeostasis by catalyzing the hydrolysis of glucose‐6‐phosphate (G6P) to glucose and phosphate in the terminal step of glycogenolysis and gluconeogenesis. Patients with GSD‐Ia manifest life‐threatening fasting hypoglycemia along with the excessive accumulation of hepatic glycogen and triglycerides which results in hepatomegaly and a risk of long‐term complications such as hepatocellular adenoma and carcinoma (HCA/HCC). The etiology of HCA/HCC development in GSD‐Ia, however, is unknown. Recent studies have shown that the livers in model animals of GSD‐Ia display impairment of autophagy, a cellular recycling process which is critical for energy metabolism and cellular homeostasis. However, molecular mechanisms of autophagy impairment and its involvement in pathogenesis in GSD‐Ia are still under investigation. Here, we summarize the latest advances for signaling pathways implicated in hepatic autophagy impairment and the roles of autophagy in hepatic tumorigenesis in GSD‐Ia. In addition, recent evidence has illustrated that autophagy plays an important role in hepatic metabolism and liver‐directed gene therapy mediated by recombinant adeno‐associated virus (rAAV). Therefore, we highlight the possible role of hepatic autophagy in metabolic control and rAAV‐mediated gene therapy for GSD‐Ia. In this review, we also provide potential therapeutic strategies for GSD‐Ia on the basis of molecular mechanisms underlying hepatic autophagy impairment in GSD‐Ia.

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Bezafibrate Enhances AAV Vector-Mediated Genome Editing in Glycogen Storage Disease Type Ia

Cited by 7 publications

References 40 publications

Glycogen storage disease type I: Genetic etiology, clinical manifestations, and conventional and gene therapies

Glycogen storage disease type I: Genetic etiology, clinical manifestations, and conventional and gene therapies

Gene therapy for glycogen storage diseases

Emerging roles of autophagy in hepatic tumorigenesis and therapeutic strategies in glycogen storage disease type Ia: A review

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