Glucose-6-phosphate transporter gene therapy corrects metabolic and myeloid abnormalities in glycogen storage disease type Ib mice

Yiu, Wai Han; Pan, Chi-Jiunn; M, Allamarvdasht; Kim, Sang Hyun; Chou, Janice Y.

doi:10.1038/sj.gt.3302869

Cited by 35 publications

(38 citation statements)

References 33 publications

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“…The 70 -80% decrease in G6P hydrolysis in intact liver microsomes from G6PT1 ASO-treated ob/ob mice is similar to the level of hepatic G6Pase activity restored in G6PC-␣ knock-out animals by G6PC-␣ gene-bearing recombinant adenovirus treatment (23,24) and in G6PT1 knock-out mice by G6PT1 gene-bearing recombinant adenovirus treatment (25). These gene therapy approaches restore G6Pase activity in the liver to 19 -38% of that in wild-type mice, which is sufficient to normalize plasma glucose, cholesterol, triglycerides, and uric acid levels (23)(24)(25). Furthermore, in the G6PT1 ASO-treated ob/ob mice, the reduction of G6PT1 activity resulted in a compensatory increase in hepatic G6PC-␣ levels and G6PC activity in detergent-disrupted liver microsomes.…”

Section: Discussionmentioning

confidence: 55%

“…However, our results differed from those obtained with liver microsomes from patients with GSD-1b (39 -41) and from G6PT1 knock-out mice (42), in which G6P transport was abolished. Notably, however, the G6PT1 ASO hepatic microsome results mirror G6P uptake data from G6PT1 knock-out mice infused with adenoviral vector-containing G6PT1, where partial G6PT1 replenishment enabled some G6P transport (25). Thus, although reducing G6PT1 levels lowered blood glucose levels in diabetic rodents, maintaining some capacity to hydrolyze G6P is likely important because severe hypoglycemia and metabolic acidosis occur in animals and humans with GSD caused by the complete loss of a functioning G6Pase system (reviewed in Refs.…”

Section: Resultsmentioning

confidence: 99%

“…Section 1734 solely to indicate this fact. ment of G6Pase activity in rodent models of GSD via adenovirus-mediated gene therapy can normalize plasma glucose, cholesterol, and triglyceride concentrations and dramatically reduce liver and kidney enlargement and glycogen deposition in these organs (23)(24)(25). Thus, because of its key regulatory role in hepatic glucose production and because only limited G6Pase activity is needed to avoid complications of GSD, we chose to test the hypothesis that reducing the activity of the G6Pase system would improve hyperglycemia in diabetes using 2Ј-O-(2-methoxy)ethyl-modified phosphorothioate antisense oligonucleotides (ASOs) specific to G6PT1.…”

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confidence: 99%

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Specific Reduction of Hepatic Glucose 6-Phosphate Transporter-1 Ameliorates Diabetes while Avoiding Complications of Glycogen Storage Disease

Sloop

Showalter

Cox

et al. 2007

Journal of Biological Chemistry

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D-Glucose-6-phosphatase is a key regulator of endogenous glucose production, and its inhibition may improve glucose control in type 2 diabetes. Herein, 2-O-(2-methoxy)ethyl-modified phosphorothioate antisense oligonucleotides (ASOs) specific to the glucose 6-phosphate transporter-1 (G6PT1) enabled reduction of hepatic D-Glu-6-phosphatase activity in diabetic ob/ob mice. Treatment with G6PT1 ASOs decreased G6PT1 expression, reduced G6PT1 activity, blunted glucagon-stimulated glucose production, and lowered plasma glucose concentration in a dose-dependent manner. In contrast to G6PT1 knock-out mice and patients with glycogen storage disease, excess hepatic and renal glycogen accumulation, hyperlipidemia, neutropenia, and elevations in plasma lactate and uric acid did not occur. In addition, hypoglycemia was not observed in animals during extended periods of fasting, and the ability of G6PT1 ASOtreated mice to recover from an exogenous insulin challenge was not impaired. Together, these results demonstrate that effective glucose lowering by G6PT1 inhibitors can be achieved without adversely affecting carbohydrate and lipid metabolism.Hepatic control of glucose homeostasis is achieved by coordinating signaling pathways that regulate glycogen synthesis, glycogenolysis, and gluconeogenesis (1-3). During nutrient intake, D-glucose is taken up from the circulation into hepatocytes by the GLUT2 transporter. Glucokinase/hexokinase-4 phosphorylates D-glucose at C-6, yielding D-glucose 6-phosphate (G6P), 2 which is converted into D-glucose 1-phosphate for glycogen synthesis and into fructose 6-phosphate for lipid and amino acid synthesis and energy metabolism. In the postabsorptive state, glycogen phosphorylase catalyzes the release of glucose from chains of glycogen, and as this supply is depleted, de novo glucose is synthesized from lactate, amino acids, and glycerol via the process of gluconeogenesis. The end product of both glycogenolysis and gluconeogenesis is G6P, which must be hydrolyzed by D-glucose-6-phosphatase (G6Pase) to yield D-glucose that can be released into the bloodstream. Together, the combined net flux through glucokinase and G6Pase determines the contribution of the liver to whole body glucose homeostasis.G6Pase is a multicomponent enzyme anchored in the endoplasmic reticulum that is composed of membrane-spanning catalytic (G6PC-␣ and/or G6PC-␤) (4 -8) and transport (G6PT1, G6PT2, and G6PT3) subunits (9 -11). The G6Pase substrate transport model proposes that the active site of G6PC is located on the cisternal surface of the endoplasmic reticulum lumen (12-14). The T1 transporter shuttles intracellular G6P across the endoplasmic reticulum membrane into the lumen, where it is hydrolyzed, and the T2 and T3 transporters mediate export of P i and glucose, respectively, back to the cytoplasm (13, 15, 16).Inability to suppress hepatic glucose production because of insulin deficiency or resistance is a key defect in diabetes, and thus, attempts to develop molecules that inhibit glycogenolytic or gluconeogenic ...

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Section: Discussionmentioning

confidence: 55%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Specific Reduction of Hepatic Glucose 6-Phosphate Transporter-1 Ameliorates Diabetes while Avoiding Complications of Glycogen Storage Disease

Sloop

Showalter

Cox

et al. 2007

Journal of Biological Chemistry

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“…Long-Evans cinnamon rats are a model of Wilson disease and transfer of the ATP7B gene to hepatocytes ameliorates both biochemical and histological pathologies [165]. Transgene products released into blood circulation after successful gene transfer into the hepatocytes corrected pathological manifestation both inside and/or outside of the liver in glycogen storage diseases (type Ia, [166] Ib [167] and II [167], mucopolysaccharidosis type I [168], IIIB [169] and VII [170], hereditary tyrosinemia type I [171], UDP glucuronyltransferase deficiency (Crigler-Najjar type I) [172], and hemophilia [173][174][175].…”

Section: Preclinical Evaluationmentioning

confidence: 99%

Regenerative Therapies for Liver Diseases

Sharma

Rittelmeyer

Cantz

et al. 2012

Regenerative Medicine and Cell Therapy

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The liver responds to injury or tissue loss by rapid restoration of the original cell mass. The high regenerative capacity is sufficient to restore normal volume and function in most forms of acute liver injury and medical interventions are not required. For the development of regenerative therapies a fundamental understanding of these regenerative principles in the liver is required. In this chapter, we discuss the emerging medical approaches for acute liver failure, chronic liver failure, and hereditary liver diseases, which are based on technologies, such as (stem) cell therapy, tissue engineering, bio-artificial devices or gene therapies. Principles of Liver RegenerationThe liver comprises about one-fiftieth of the total adult body weight [1], receives approximately 25 % of cardiac output [2] and consists of an exceptional anatomical structure in both biliary system and vasculature. The biliary system,

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“…[40] Gene therapy is in the early stages of research in animals. [41] Dietary management is less demanding for GSD type III. If hypoglycemia is present, frequent meals high in carbohydrates with cornstarch supplements, or nocturnal gastric drip feedings, are usually effective.…”

Section: Gsdsmentioning

confidence: 99%

Medical Management of Chronic Liver Diseases in Children (Part I)

El-Shabrawi

Kamal

2011

Pediatric Drugs

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The management of children with chronic liver disease (CLD) mandates a multidisciplinary approach. CLDs can be classified into 'potentially' curable, treatable non-curable, and end-stage diseases. Goals pertaining to the management of CLDs can be divided into prevention or minimization of progressive liver damage in curable CLD by treating the primary cause; prevention or control of complications in treatable CLD; and prediction of the outcome in end-stage CLD in order to deliver definitive therapy by surgical procedures, including liver transplantation. Curative, specific therapies aimed at the primary causes of CLDs are, if possible, best considered by a pediatric hepatologist. Medical management of CLDs in children will be reviewed in two parts, with part I (this article) specifically focusing on 'potentially' curable CLDs. Dietary modification is the cornerstone of management for galactosemia, hereditary fructose intolerance, and certain glycogen storage diseases, as well as non-alcoholic steatohepatitis. It is also essential in tyrosinemia, in addition to nitisinone [2-(nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione] therapy, as well as in Wilson disease along with copper-chelating agents such as D-penicillamine, triethylenetetramine dihydrochloride, and ammonium tetrathiomolybdate. Zinc and antioxidants are adjuvant drugs in Wilson disease. New advances in chronic viral hepatitis have been made with the advent of oral antivirals. In children, currently available drugs for the treatment of chronic hepatitis B virus infection are standard interferon (IFN)-α-2, pegylated IFN-α-2 (PG-IFN), and lamivudine. In adults, adefovir and entecavir have also been licensed, whereas telbivudine, emtricitabine, tenofovir disoproxil fumarate, clevudine, and thymosin α-1 are currently undergoing clinical testing. For chronic hepatitis C virus infection, the most accepted treatment is PG-IFN plus ribavirin. Corticosteroids, with or without azathioprine, remain the basic strategy for inducing remission in autoimmune hepatitis. Ciclosporin (cyclosporine) and other immune suppressants may be used for patients who do not achieve remission, or who have significant side effects, with corticosteroid/azathioprine therapy. The above therapies can prevent, or at least minimize, progression of liver damage, particularly if started early, leading to an almost normal quality of life in affected children.

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Glucose-6-phosphate transporter gene therapy corrects metabolic and myeloid abnormalities in glycogen storage disease type Ib mice

Cited by 35 publications

References 33 publications

Specific Reduction of Hepatic Glucose 6-Phosphate Transporter-1 Ameliorates Diabetes while Avoiding Complications of Glycogen Storage Disease

Specific Reduction of Hepatic Glucose 6-Phosphate Transporter-1 Ameliorates Diabetes while Avoiding Complications of Glycogen Storage Disease

Regenerative Therapies for Liver Diseases

Medical Management of Chronic Liver Diseases in Children (Part I)

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