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Janice Y. Chou - One of the best experts on this subject based on the ideXlab platform.

  • Correction of metabolic abnormalities in a mouse model of glycogen storage disease type Ia by CRISPR/Cas9-based gene editing.
    Molecular therapy : the journal of the American Society of Gene Therapy, 2020
    Co-Authors: Irina Arnaoutova, Lisa Zhang, Brian C. Mansfield, Hung-dar Chen, Janice Y. Chou
    Abstract:

    Glycogen storage disease type Ia (GSD-Ia), deficient in glucose-6-phosphatase-α (G6PC), is characterized by impaired glucose homeostasis and a hallmark of fasting hypoglycemia. We have developed a recombinant adeno-associated virus (rAAV) vector-mediated gene therapy for GSD-Ia that is currently in a phase I/II clinical trial. While therapeutic expression of the episomal rAAV-G6PC clinical vector is stable in mice, the long-term durability of expression in humans is currently being established. Here we evaluated CRISPR/Cas9-based in vivo genome editing technology to correct a prevalent pathogenic human variant, G6PC-p.R83C. We have generated a homozygous G6PC-R83C mouse strain and shown that the G6PC-R83C mice manifest impaired glucose homeostasis and frequent hypoglycemic seizures, mimicking the pathophysiology of GSD-Ia patients. We then used a CRISPR/Cas9-based gene editing system to treat newborn G6PC-R83C mice and showed that the treated mice grew normally to age 16 weeks without hypoglycemia seizures. The treated G6PC-R83C mice, expressing ≥ 3% of normal hepatic G6Pase-α activity, maintained glucose homeostasis, displayed normalized blood metabolites, and could sustain 24 h of fasting. Taken together, we have developed a second-generation therapy in which in vivo correction of a pathogenic G6PC-p.R83C variant in its native genetic locus could lead to potentially permanent, durable, long-term correction of the GSD-Ia phenotype.

  • gene therapy using a novel G6PC s298c variant enhances the long term efficacy for treating glycogen storage disease type ia
    Biochemical and Biophysical Research Communications, 2020
    Co-Authors: Lisa Zhang, Brian C. Mansfield, Javier Anduaga, Matthew F Starost, Cheol Woo Lee, Irina Arnaoutova, Janice Y. Chou
    Abstract:

    The current phase I/II clinical trial for human glycogen storage disease type-Ia (GSD-Ia) (NCT03517085) uses a recombinant adeno-associated virus (rAAV) vector expressing a codon-optimized human glucose-6-phosphatase-α (G6Pase-α or G6PC). DNA sequence changes introduced by codon-optimization can negatively impact gene expression. We therefore generated a novel variant in which a single amino acid change, S298C, is introduced into the native human G6PC sequence. Short term gene transfer study in G6PC-/- mice showed that the rAAV-G6PC-S298C vector is 3-fold more efficacious than the native rAAV-G6PC vector. We have shown previously that restoring 3% of normal hepatic G6Pase-α activity in G6PC-/- mice prevents hepatocellular adenoma/carcinoma (HCA/HCC) development and that mice harboring <3% of normal hepatic G6Pase-α activity are at risk of tumor development. We have also shown that G6Pase-α deficiency leads to hepatic autophagy impairment that can contribute to hepatocarcinogenesis. We now undertake a long-term (66-week) preclinical characterization of the rAAV-G6PC-S298C vector in GSD-Ia gene therapy. We show that the increased efficacy of rAAV-G6PC-S298C has enabled the G6PC-/- mice treated with a lower dose of this vector to survive long-term. We further show that mice expressing ≥3% of normal hepatic G6Pase-α activity do not develop hepatic tumors or autophagy impairment but mice expressing <3% of normal hepatic G6Pase-α activity display impaired hepatic autophagy with one developing HCA/HCC nodules. Our study shows that the rAAV-G6PC-S298C vector provides equal or greater efficacy to the codon optimization approach, offering a valuable alternative vector for clinical translation in human GSD-Ia.

  • gene therapy using a novel G6PC s298c variant enhances the long term efficacy for treating glycogen storage disease type ia
    Biochemical and Biophysical Research Communications, 2020
    Co-Authors: Lisa Zhang, Brian C. Mansfield, Javier Anduaga, Matthew F Starost, Cheol Woo Lee, Irina Arnaoutova, Janice Y. Chou
    Abstract:

    Abstract The current phase I/II clinical trial for human glycogen storage disease type-Ia (GSD-Ia) (NCT 03517085) uses a recombinant adeno-associated virus (rAAV) vector expressing a codon-optimized human glucose-6-phosphatase-α (G6Pase-α or G6PC). DNA sequence changes introduced by codon-optimization can negatively impact gene expression. We therefore generated a novel variant in which a single amino acid change, S298C, is introduced into the native human G6PC sequence. Short term gene transfer study in G6PC−/− mice showed that the rAAV-G6PC-S298C vector is 3-fold more efficacious than the native rAAV-G6PC vector. We have shown previously that restoring 3% of normal hepatic G6Pase-α activity in G6PC−/− mice prevents hepatocellular adenoma/carcinoma (HCA/HCC) development and that mice harboring

  • the signaling pathways implicated in impairment of hepatic autophagy in glycogen storage disease type ia
    Human Molecular Genetics, 2020
    Co-Authors: Sudeep Gautam, Brian C. Mansfield, Lisa Zhang, Cheol Woo Lee, Irina Arnaoutova, Janice Y. Chou
    Abstract:

    Glucose-6-phosphatase-α (G6Pase-α or G6PC) deficiency in glycogen storage disease type-Ia (GSD-Ia) leads to impaired hepatic autophagy, a recycling process important for cellular metabolism and homeostasis. Autophagy can be regulated by several energy sensing pathways, including sirtuin 1 (SIRT1), forkhead box O (FoxO), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-α (PPAR-α), and mammalian target of rapamycin (mTOR). Using 10-day old global G6PC-deficient (G6PC-/-) mice, hepatic autophagy impairment was attributed to activation of mTOR and inhibition of AMPK signaling. In other studies, using adult liver-specific G6PC-deficient mice at both pre-tumor and tumor stages, hepatic autophagy impairment was attributed to downregulation of SIRT1 signaling and mTOR was not implicated. In this study, we provide a detailed analysis of the major autophagy pathways in young G6PC-/- mice over the first 4 weeks of life. We show that impaired SIRT1, FoxO3a, AMPK, and PPAR-α signaling are responsible for autophagy impairment but mTOR is involved minimally. Hepatic SIRT1 overexpression corrects defective autophagy, restores the expression of FoxO3a and liver kinase B1 but fails to normalize impaired PPAR-α expression or metabolic abnormalities associated with GSD-Ia. Importantly, restoration of hepatic G6Pase-α expression in G6PC-/- mice corrects defective autophagy, restores SIRT1/FoxO3a/AMPK/PPAR-α signaling and rectifies metabolic abnormalities. Taken together, these data show that hepatic autophagy impairment in GSD-Ia is mediated by downregulation of SIRT1/FoxO3a/AMPK/PPAR-α signaling.

  • an evolutionary approach to optimizing glucose 6 phosphatase α enzymatic activity for gene therapy of glycogen storage disease type ia
    Journal of Inherited Metabolic Disease, 2019
    Co-Authors: Lisa Zhang, Jun-ho Cho, Brian C. Mansfield, Irina Arnaoutova, Janice Y. Chou
    Abstract:

    Glycogen storage disease type-Ia (GSD-Ia), caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC), is characterized by impaired glucose homeostasis with a hallmark hypoglycemia, following a short fast. We have shown that G6PC-deficient (G6PC-/-) mice treated with recombinant adeno-associated virus (rAAV) vectors expressing either wild-type (WT) (rAAV-hG6PC-WT) or codon-optimized (co) (rAAV-co-hG6PC) human (h) G6Pase-α maintain glucose homeostasis if they restore ≥3% of normal hepatic G6Pase-α activity. The co vector, which has a higher potency, is currently being used in a phase I/II clinical trial for human GSD-Ia (NCT03517085). While routinely used in clinical therapies, co vectors may not always be optimal. Codon-optimization can impact RNA secondary structure, change RNA/DNA protein-binding sites, affect protein conformation and function, and alter posttranscriptional modifications that may reduce potency or efficacy. We therefore sought to develop alternative approaches to increase the potency of the G6PC gene transfer vectors. Using an evolutionary sequence analysis, we identified a Ser-298 to Cys-298 substitution naturally found in canine, mouse, rat, and several primate G6Pase-α isozymes, that when incorporated into the WT hG6Pase-α sequence, markedly enhanced enzymatic activity. Using G6PC-/- mice, we show that the efficacy of the rAAV-hG6PC-S298C vector was 3-fold higher than that of the rAAV-hG6PC-WT vector. The rAAV-hG6PC-S298C vector with increased efficacy, that minimizes the potential problems associated with codon-optimization, offers a valuable vector for clinical translation in human GSD-Ia.

Brian C. Mansfield - One of the best experts on this subject based on the ideXlab platform.

  • Correction of metabolic abnormalities in a mouse model of glycogen storage disease type Ia by CRISPR/Cas9-based gene editing.
    Molecular therapy : the journal of the American Society of Gene Therapy, 2020
    Co-Authors: Irina Arnaoutova, Lisa Zhang, Brian C. Mansfield, Hung-dar Chen, Janice Y. Chou
    Abstract:

    Glycogen storage disease type Ia (GSD-Ia), deficient in glucose-6-phosphatase-α (G6PC), is characterized by impaired glucose homeostasis and a hallmark of fasting hypoglycemia. We have developed a recombinant adeno-associated virus (rAAV) vector-mediated gene therapy for GSD-Ia that is currently in a phase I/II clinical trial. While therapeutic expression of the episomal rAAV-G6PC clinical vector is stable in mice, the long-term durability of expression in humans is currently being established. Here we evaluated CRISPR/Cas9-based in vivo genome editing technology to correct a prevalent pathogenic human variant, G6PC-p.R83C. We have generated a homozygous G6PC-R83C mouse strain and shown that the G6PC-R83C mice manifest impaired glucose homeostasis and frequent hypoglycemic seizures, mimicking the pathophysiology of GSD-Ia patients. We then used a CRISPR/Cas9-based gene editing system to treat newborn G6PC-R83C mice and showed that the treated mice grew normally to age 16 weeks without hypoglycemia seizures. The treated G6PC-R83C mice, expressing ≥ 3% of normal hepatic G6Pase-α activity, maintained glucose homeostasis, displayed normalized blood metabolites, and could sustain 24 h of fasting. Taken together, we have developed a second-generation therapy in which in vivo correction of a pathogenic G6PC-p.R83C variant in its native genetic locus could lead to potentially permanent, durable, long-term correction of the GSD-Ia phenotype.

  • gene therapy using a novel G6PC s298c variant enhances the long term efficacy for treating glycogen storage disease type ia
    Biochemical and Biophysical Research Communications, 2020
    Co-Authors: Lisa Zhang, Brian C. Mansfield, Javier Anduaga, Matthew F Starost, Cheol Woo Lee, Irina Arnaoutova, Janice Y. Chou
    Abstract:

    The current phase I/II clinical trial for human glycogen storage disease type-Ia (GSD-Ia) (NCT03517085) uses a recombinant adeno-associated virus (rAAV) vector expressing a codon-optimized human glucose-6-phosphatase-α (G6Pase-α or G6PC). DNA sequence changes introduced by codon-optimization can negatively impact gene expression. We therefore generated a novel variant in which a single amino acid change, S298C, is introduced into the native human G6PC sequence. Short term gene transfer study in G6PC-/- mice showed that the rAAV-G6PC-S298C vector is 3-fold more efficacious than the native rAAV-G6PC vector. We have shown previously that restoring 3% of normal hepatic G6Pase-α activity in G6PC-/- mice prevents hepatocellular adenoma/carcinoma (HCA/HCC) development and that mice harboring <3% of normal hepatic G6Pase-α activity are at risk of tumor development. We have also shown that G6Pase-α deficiency leads to hepatic autophagy impairment that can contribute to hepatocarcinogenesis. We now undertake a long-term (66-week) preclinical characterization of the rAAV-G6PC-S298C vector in GSD-Ia gene therapy. We show that the increased efficacy of rAAV-G6PC-S298C has enabled the G6PC-/- mice treated with a lower dose of this vector to survive long-term. We further show that mice expressing ≥3% of normal hepatic G6Pase-α activity do not develop hepatic tumors or autophagy impairment but mice expressing <3% of normal hepatic G6Pase-α activity display impaired hepatic autophagy with one developing HCA/HCC nodules. Our study shows that the rAAV-G6PC-S298C vector provides equal or greater efficacy to the codon optimization approach, offering a valuable alternative vector for clinical translation in human GSD-Ia.

  • gene therapy using a novel G6PC s298c variant enhances the long term efficacy for treating glycogen storage disease type ia
    Biochemical and Biophysical Research Communications, 2020
    Co-Authors: Lisa Zhang, Brian C. Mansfield, Javier Anduaga, Matthew F Starost, Cheol Woo Lee, Irina Arnaoutova, Janice Y. Chou
    Abstract:

    Abstract The current phase I/II clinical trial for human glycogen storage disease type-Ia (GSD-Ia) (NCT 03517085) uses a recombinant adeno-associated virus (rAAV) vector expressing a codon-optimized human glucose-6-phosphatase-α (G6Pase-α or G6PC). DNA sequence changes introduced by codon-optimization can negatively impact gene expression. We therefore generated a novel variant in which a single amino acid change, S298C, is introduced into the native human G6PC sequence. Short term gene transfer study in G6PC−/− mice showed that the rAAV-G6PC-S298C vector is 3-fold more efficacious than the native rAAV-G6PC vector. We have shown previously that restoring 3% of normal hepatic G6Pase-α activity in G6PC−/− mice prevents hepatocellular adenoma/carcinoma (HCA/HCC) development and that mice harboring

  • the signaling pathways implicated in impairment of hepatic autophagy in glycogen storage disease type ia
    Human Molecular Genetics, 2020
    Co-Authors: Sudeep Gautam, Brian C. Mansfield, Lisa Zhang, Cheol Woo Lee, Irina Arnaoutova, Janice Y. Chou
    Abstract:

    Glucose-6-phosphatase-α (G6Pase-α or G6PC) deficiency in glycogen storage disease type-Ia (GSD-Ia) leads to impaired hepatic autophagy, a recycling process important for cellular metabolism and homeostasis. Autophagy can be regulated by several energy sensing pathways, including sirtuin 1 (SIRT1), forkhead box O (FoxO), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-α (PPAR-α), and mammalian target of rapamycin (mTOR). Using 10-day old global G6PC-deficient (G6PC-/-) mice, hepatic autophagy impairment was attributed to activation of mTOR and inhibition of AMPK signaling. In other studies, using adult liver-specific G6PC-deficient mice at both pre-tumor and tumor stages, hepatic autophagy impairment was attributed to downregulation of SIRT1 signaling and mTOR was not implicated. In this study, we provide a detailed analysis of the major autophagy pathways in young G6PC-/- mice over the first 4 weeks of life. We show that impaired SIRT1, FoxO3a, AMPK, and PPAR-α signaling are responsible for autophagy impairment but mTOR is involved minimally. Hepatic SIRT1 overexpression corrects defective autophagy, restores the expression of FoxO3a and liver kinase B1 but fails to normalize impaired PPAR-α expression or metabolic abnormalities associated with GSD-Ia. Importantly, restoration of hepatic G6Pase-α expression in G6PC-/- mice corrects defective autophagy, restores SIRT1/FoxO3a/AMPK/PPAR-α signaling and rectifies metabolic abnormalities. Taken together, these data show that hepatic autophagy impairment in GSD-Ia is mediated by downregulation of SIRT1/FoxO3a/AMPK/PPAR-α signaling.

  • an evolutionary approach to optimizing glucose 6 phosphatase α enzymatic activity for gene therapy of glycogen storage disease type ia
    Journal of Inherited Metabolic Disease, 2019
    Co-Authors: Lisa Zhang, Jun-ho Cho, Brian C. Mansfield, Irina Arnaoutova, Janice Y. Chou
    Abstract:

    Glycogen storage disease type-Ia (GSD-Ia), caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC), is characterized by impaired glucose homeostasis with a hallmark hypoglycemia, following a short fast. We have shown that G6PC-deficient (G6PC-/-) mice treated with recombinant adeno-associated virus (rAAV) vectors expressing either wild-type (WT) (rAAV-hG6PC-WT) or codon-optimized (co) (rAAV-co-hG6PC) human (h) G6Pase-α maintain glucose homeostasis if they restore ≥3% of normal hepatic G6Pase-α activity. The co vector, which has a higher potency, is currently being used in a phase I/II clinical trial for human GSD-Ia (NCT03517085). While routinely used in clinical therapies, co vectors may not always be optimal. Codon-optimization can impact RNA secondary structure, change RNA/DNA protein-binding sites, affect protein conformation and function, and alter posttranscriptional modifications that may reduce potency or efficacy. We therefore sought to develop alternative approaches to increase the potency of the G6PC gene transfer vectors. Using an evolutionary sequence analysis, we identified a Ser-298 to Cys-298 substitution naturally found in canine, mouse, rat, and several primate G6Pase-α isozymes, that when incorporated into the WT hG6Pase-α sequence, markedly enhanced enzymatic activity. Using G6PC-/- mice, we show that the efficacy of the rAAV-hG6PC-S298C vector was 3-fold higher than that of the rAAV-hG6PC-WT vector. The rAAV-hG6PC-S298C vector with increased efficacy, that minimizes the potential problems associated with codon-optimization, offers a valuable vector for clinical translation in human GSD-Ia.

Gilles Mithieux - One of the best experts on this subject based on the ideXlab platform.

  • Glycogen storage disease type 1a is associated with disturbed vitamin A metabolism and elevated serum retinol levels
    Human Molecular Genetics, 2020
    Co-Authors: Ali Saeed, Janette Heegsma, Joanne Hoogerland, Hanna Wessel, Terry Derks, Eveline Van Der Veer, Gilles Mithieux, Fabienne Rajas, Maaike Oosterveer, Klaas Nico Faber
    Abstract:

    Glycogen storage disease type 1a (GSD Ia) is an inborn error of metabolism caused by mutations in the G6PC gene, encoding the catalytic subunit of glucose-6-phosphatase. Early symptoms include severe fasting intolerance, failure to thrive and hepatomegaly, biochemically associated with nonketotic hypoglycemia, fasting hyperlactidemia, hyperuricemia and hyperlipidemia. Dietary management is the cornerstone of treatment aiming at maintaining euglycemia, prevention of secondary metabolic perturbations and long-term complications, including liver (hepatocellular adenomas and carcinomas), kidney and bone disease (hypovitaminosis D and osteoporosis). As impaired vitamin A homeostasis also associates with similar symptoms and is coordinated by the liver, we here analysed whether vitamin A metabolism is affected in GSD Ia patients and liver-specific G6PC-/- knock-out mice. Serum levels of retinol and retinol binding protein 4 (RBP4) were significantly increased in both GSD Ia patients and L-G6PC-/- mice. In contrast, hepatic retinol levels were significantly reduced in L-G6PC-/- mice, while hepatic retinyl palmitate (vitamin A storage form) and RBP4 levels were not altered. Transcript and protein analyses indicate an enhanced production of retinol and reduced conversion the retinoic acids (unchanged LRAT, Pnpla2/ATGL and Pnpla3 up, Cyp26a1 down) in L-G6PC-/- mice. Aberrant expression of genes involved in vitamin A metabolism was associated with reduced basal messenger RNA levels of markers of inflammation (Cd68, Tnfα, Nos2, Il-6) and fibrosis (Col1a1, Acta2, Tgfβ, Timp1) in livers of L-G6PC-/- mice. In conclusion, GSD Ia is associated with elevated serum retinol and RBP4 levels, which may contribute to disease symptoms, including osteoporosis and hepatic steatosis.

  • pathogenesis of hepatic tumors following gene therapy in murine and canine models of glycogen storage disease
    Molecular therapy. Methods & clinical development, 2019
    Co-Authors: Hye-ri Kang, Elizabeth D Brooks, Lauren R Waskowicz, Monika Gjorgjieva, Stephanie Smith, Zelin Chen, Shawn M Burgess, Randy J Chandler, Kylie M Grady, Gilles Mithieux
    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

  • The role of kidney in the inter-organ coordination of endogenous glucose production during fasting
    Molecular metabolism, 2018
    Co-Authors: Keizo Kaneko, Fabienne Rajas, Amandine Gautier-stein, Maud Soty, Carine Zitoun, Adeline Duchampt, Marine Silva, Erwann Philippe, Gilles Mithieux
    Abstract:

    OBJECTIVE: The respective contributions to endogenous glucose production (EGP) of the liver, kidney and intestine vary during fasting. We previously reported that the deficiency in either hepatic or intestinal gluconeogenesis modulates the repartition of EGP via glucagon secretion (humoral factor) and gut-brain-liver axis (neural factor), respectively. Considering renal gluconeogenesis reportedly accounted for approximately 50% of EGP during fasting, we examined whether a reduction in renal gluconeogenesis could promote alterations in the repartition of EGP in this situation. METHODS: We studied mice whose glucose-6-phosphatase (G6Pase) catalytic subunit (G6PC) is specifically knocked down in the kidneys (K-G6PC-/- mice) during fasting. We also examined the additional effects of intestinal G6PC deletion, renal denervation and vitamin D administration on the altered glucose metabolism in K-G6PC-/- mice. RESULTS: Compared with WT mice, K-G6PC-/- mice exhibited (1) lower glycemia, (2) enhanced intestinal but not hepatic G6Pase activity, (3) enhanced hepatic glucokinase (GK encoded by Gck) activity, (4) increased hepatic glucose-6-phosphate and (5) hepatic glycogen spared from exhaustion during fasting. Increased hepatic Gck expression in the post-absorptive state could be dependent on the enhancement of insulin signal (AKT phosphorylation) in K-G6PC-/- mice. In contrast, the increase in hepatic GK activity was not observed in mice with both kidney- and intestine-knockout (KI-G6PC-/- mice). Hepatic Gck gene expression and hepatic AKT phosphorylation were reduced in KI-G6PC-/- mice. Renal denervation by capsaicin did not induce any effect on glucose metabolism in K-G6PC-/- mice. Plasma level of 1,25 (OH)2 D3, an active form of vitamin D, was decreased in K-G6PC-/- mice. Interestingly, the administration of 1,25 (OH)2 D3 prevented the enhancement of intestinal gluconeogenesis and hepatic GK activity and blocked the accumulation of hepatic glycogen otherwise observed in K-G6PC-/- mice during fasting. CONCLUSIONS: A diminution in renal gluconeogenesis that is accompanied by a decrease in blood vitamin D promotes a novel repartition of EGP among glucose producing organs during fasting, featured by increased intestinal gluconeogenesis that leads to sparing glycogen stores in the liver. Our data suggest a possible involvement of a crosstalk between the kidneys and intestine (via the vitamin D system) and the intestine and liver (via a neural gut-brain axis), which might take place in the situations of deficient renal glucose production, such as chronic kidney disease.

  • The role of kidney in the inter-organ coordination of endogenous glucose production during fasting
    Elsevier, 2018
    Co-Authors: Keizo Kaneko, Fabienne Rajas, Amandine Gautier-stein, Maud Soty, Carine Zitoun, Adeline Duchampt, Marine Silva, Erwann Philippe, Gilles Mithieux
    Abstract:

    Objective: The respective contributions to endogenous glucose production (EGP) of the liver, kidney and intestine vary during fasting. We previously reported that the deficiency in either hepatic or intestinal gluconeogenesis modulates the repartition of EGP via glucagon secretion (humoral factor) and gut–brain–liver axis (neural factor), respectively. Considering renal gluconeogenesis reportedly accounted for approximately 50% of EGP during fasting, we examined whether a reduction in renal gluconeogenesis could promote alterations in the repartition of EGP in this situation. Methods: We studied mice whose glucose-6-phosphatase (G6Pase) catalytic subunit (G6PC) is specifically knocked down in the kidneys (K-G6PC-/- mice) during fasting. We also examined the additional effects of intestinal G6PC deletion, renal denervation and vitamin D administration on the altered glucose metabolism in K-G6PC-/- mice. Results: Compared with WT mice, K-G6PC-/- mice exhibited (1) lower glycemia, (2) enhanced intestinal but not hepatic G6Pase activity, (3) enhanced hepatic glucokinase (GK encoded by Gck) activity, (4) increased hepatic glucose-6-phosphate and (5) hepatic glycogen spared from exhaustion during fasting. Increased hepatic Gck expression in the post-absorptive state could be dependent on the enhancement of insulin signal (AKT phosphorylation) in K-G6PC-/- mice. In contrast, the increase in hepatic GK activity was not observed in mice with both kidney- and intestine-knockout (KI-G6PC-/- mice). Hepatic Gck gene expression and hepatic AKT phosphorylation were reduced in KI-G6PC-/- mice. Renal denervation by capsaicin did not induce any effect on glucose metabolism in K-G6PC-/- mice. Plasma level of 1,25 (OH)2 D3, an active form of vitamin D, was decreased in K-G6PC-/- mice. Interestingly, the administration of 1,25 (OH)2 D3 prevented the enhancement of intestinal gluconeogenesis and hepatic GK activity and blocked the accumulation of hepatic glycogen otherwise observed in K-G6PC-/- mice during fasting. Conclusions: A diminution in renal gluconeogenesis that is accompanied by a decrease in blood vitamin D promotes a novel repartition of EGP among glucose producing organs during fasting, featured by increased intestinal gluconeogenesis that leads to sparing glycogen stores in the liver. Our data suggest a possible involvement of a crosstalk between the kidneys and intestine (via the vitamin D system) and the intestine and liver (via a neural gut-brain axis), which might take place in the situations of deficient renal glucose production, such as chronic kidney disease. Keywords: Endogenous glucose production, Gluconeogenesis, Hypoglycemia, Glycogen, Chronic kidney disease, Vitamin

  • Hepatocytes contribute to residual glucose production in a mouse model for glycogen storage disease type Ia
    Hepatology, 2017
    Co-Authors: Brenda Hijmans, Gilles Mithieux, Maud Soty, Andreas Boss, Theo Van Dijk, Henk Wolters, Élodie Mutel, Albert Groen, Terry G.j. Derks, Arend Heerschap
    Abstract:

    It is a long-standing enigma how glycogen storage disease (GSD) type I patients retain a limited capacity for endogenous glucose production despite the loss of glucose-6-phosphatase activity. Insight into the source of residual endogenous glucose production is of clinical importance given the risk of sudden death in these patients, but so far contradictory mechanisms have been proposed. We investigated glucose-6-phosphatase-independent endogenous glucose production in hepatocytes isolated from a liver-specific GSD Ia mouse model (L-G6PC-/- mice) and performed real-time analysis of hepatic glucose fluxes and glycogen metabolism in L-G6PC-/- mice using state-of-the-art stable isotope methodologies. Here we show that G6PC-deficient hepatocytes are capable of producing glucose. In vivo analysis of hepatic glucose metabolism revealed that the hepatic glucokinase flux was decreased by 95% in L-G6PC-/- mice. It also showed increased glycogen phosphorylase flux in L-G6PC-/- mice, which is coupled to the release of free glucose through glycogen debranching. Although the ex vivo activities of debranching enzyme and lysosomal acid maltase, two major hepatic α-glucosidases, were unaltered in L-G6PC-/- mice, pharmacological inhibition of α-glucosidase activity almost completely abolished residual glucose production by G6PC-deficient hepatocytes. CONCLUSION: Our data indicate that hepatocytes contribute to residual glucose production in GSD Ia. We show that α-glucosidase activity, i.e. glycogen debranching and/or lysosomal glycogen breakdown, contributes to residual glucose production by GSD Ia hepatocytes. A strong reduction in hepatic GCK flux in L-G6PC-/- mice furthermore limits the phosphorylation of free glucose synthesized by G6PC-deficient hepatocytes, allowing the release of glucose into the circulation. The almost complete abrogation of GCK flux in G6PC-deficient liver also explains the contradictory reports on residual glucose production in GSD Ia patients. (Hepatology 2017;66:2042-2054).

Young Mok Lee - One of the best experts on this subject based on the ideXlab platform.

  • gene therapy prevents hepatic tumor initiation in murine glycogen storage disease type ia at the tumor developing stage
    Journal of Inherited Metabolic Disease, 2019
    Co-Authors: Jun-ho Cho, Brian C. Mansfield, Young Mok Lee, Matthew F Starost, Janice Y. Chou
    Abstract:

    Hepatocellular adenoma/carcinoma (HCA/HCC) is a long-term complication of glycogen storage disease type-Ia (GSD-Ia), which is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC), a key enzyme in gluconeogenesis. Currently, there is no therapy to address HCA/HCC in GSD-Ia. We have previously shown that a recombinant adeno-associated virus (rAAV) vector-mediated G6PC gene transfer to 2-week-old G6PC-/- mice prevents HCA development. However, it remains unclear whether G6PC gene transfer at the tumor developing stage of GSD-Ia can prevent tumor initiation or abrogate the pre-existing tumors. Using liver-specific G6PC-knockout (L-G6PC-/-) mice that develop HCA/HCC, we now show that treating the mice at the tumor-developing stage with rAAV-G6PC restores hepatic G6Pase-α expression, normalizes glucose homeostasis, and prevents de novo HCA/HCC development. The rAAV-G6PC treatment also normalizes defective hepatic autophagy and corrects metabolic abnormalities in the nontumor liver tissues of both tumor-free and tumor-bearing mice. However, gene therapy cannot restore G6Pase-α expression in the HCA/HCC lesions and fails to abrogate any pre-existing tumors. We show that the expression of 11 β-hydroxysteroid dehydrogenase type-1 that mediates local glucocorticoid activation is downregulated in HCA/HCC lesions, leading to impairment in glucocorticoid signaling critical for gluconeogenesis activation. This suggests that local glucocorticoid action downregulation in the HCA/HCC lesions may suppress gene therapy mediated G6Pase-α restoration. Collectively, our data show that rAAV-mediated gene therapy can prevent de novo HCA/HCC development in L-G6PC-/- mice at the tumor developing stage, but it cannot reduce any pre-existing tumor burden.

  • liver directed gene therapy for murine glycogen storage disease type ib
    Human Molecular Genetics, 2017
    Co-Authors: Joonhyun Kwon, Brian C. Mansfield, Jun-ho Cho, Young Mok Lee, Goo-young Kim, Javier Anduaga, Matthew F Starost, Janice Y. Chou
    Abstract:

    Glycogen storage disease type-Ib (GSD-Ib), deficient in the glucose-6-phosphate transporter (G6PT), is characterized by impaired glucose homeostasis, myeloid dysfunction, and long-term risk of hepatocellular adenoma (HCA). We examined the efficacy of G6PT gene therapy in G6pt-/- mice using recombinant adeno-associated virus (rAAV) vectors, directed by either the G6PC or the G6PT promoter/enhancer. Both vectors corrected hepatic G6PT deficiency in murine GSD-Ib but the G6PC promoter/enhancer was more efficacious. Over a 78-week study, using dose titration of the rAAV vectors, we showed that G6pt-/- mice expressing 3-62% of normal hepatic G6PT activity exhibited a normalized liver phenotype. Two of the 12 mice expressing < 6% of normal hepatic G6PT activity developed HCA. All treated mice were leaner and more sensitive to insulin than wild-type mice. Mice expressing 3-22% of normal hepatic G6PT activity exhibited higher insulin sensitivity than mice expressing 44-62%. The levels of insulin sensitivity correlated with the magnitudes of hepatic carbohydrate response element binding protein signaling activation. In summary, we established the threshold of hepatic G6PT activity required to prevent tumor formation and showed that mice expressing 3-62% of normal hepatic G6PT activity maintained glucose homeostasis and were protected against age-related obesity and insulin resistance.

  • glycogen storage disease type ia mice with less than 2 of normal hepatic glucose 6 phosphatase α activity restored are at risk of developing hepatic tumors
    Molecular Genetics and Metabolism, 2017
    Co-Authors: Goo-young Kim, Brian C. Mansfield, Joonhyun Kwon, Jun-ho Cho, Young Mok Lee, Matthew F Starost, Chijiunn Pan, Janice Y. Chou
    Abstract:

    Glycogen storage disease type Ia (GSD-Ia), characterized by impaired glucose homeostasis and chronic risk of hepatocellular adenoma (HCA) and carcinoma (HCC), is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC). We have previously shown that G6PC-/- mice receiving gene transfer mediated by rAAV-G6PC, a recombinant adeno-associated virus (rAAV) vector expressing G6Pase-α, and expressing 3-63% of normal hepatic G6Pase-α activity maintain glucose homeostasis and do not develop HCA/HCC. However, the threshold of hepatic G6Pase-α activity required to prevent tumor formation remained unknown. In this study, we constructed rAAV-co-G6PC, a rAAV vector expressing a codon-optimized (co) G6Pase-α and showed that rAAV-co-G6PC was more efficacious than rAAV-G6PC in directing hepatic G6Pase-α expression. Over an 88-week study, we showed that both rAAV-G6PC- and rAAV-co-G6PC-treated G6PC-/- mice expressing 3-33% of normal hepatic G6Pase-α activity (AAV mice) maintained glucose homeostasis, lacked HCA/HCC, and were protected against age-related obesity and insulin resistance. Of the eleven rAAV-G6PC/rAAV-co-G6PC-treated G6PC-/- mice harboring 0.9-2.4% of normal hepatic G6Pase-α activity (AAV-low mice), 3 expressing 0.9-1.3% of normal hepatic G6Pase-α activity developed HCA/HCC, while 8 did not (AAV-low-NT). Finally, we showed that the AAV-low-NT mice exhibited a phenotype indistinguishable from that of AAV mice expressing ≥3% of normal hepatic G6Pase-α activity. The results establish the threshold of hepatic G6Pase-α activity required to prevent HCA/HCC and show that GSD-Ia mice harboring <2% of normal hepatic G6Pase-α activity are at risk of tumor development.

  • Glycogen storage disease type Ia mice with less than 2% of normal hepatic glucose-6-phosphatase-α activity restored are at risk of developing hepatic tumors.
    Molecular genetics and metabolism, 2017
    Co-Authors: Goo-young Kim, Brian C. Mansfield, Joonhyun Kwon, Jun-ho Cho, Young Mok Lee, Matthew F Starost, Chijiunn Pan, Janice Y. Chou
    Abstract:

    Glycogen storage disease type Ia (GSD-Ia), characterized by impaired glucose homeostasis and chronic risk of hepatocellular adenoma (HCA) and carcinoma (HCC), is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC). We have previously shown that G6PC-/- mice receiving gene transfer mediated by rAAV-G6PC, a recombinant adeno-associated virus (rAAV) vector expressing G6Pase-α, and expressing 3-63% of normal hepatic G6Pase-α activity maintain glucose homeostasis and do not develop HCA/HCC. However, the threshold of hepatic G6Pase-α activity required to prevent tumor formation remained unknown. In this study, we constructed rAAV-co-G6PC, a rAAV vector expressing a codon-optimized (co) G6Pase-α and showed that rAAV-co-G6PC was more efficacious than rAAV-G6PC in directing hepatic G6Pase-α expression. Over an 88-week study, we showed that both rAAV-G6PC- and rAAV-co-G6PC-treated G6PC-/- mice expressing 3-33% of normal hepatic G6Pase-α activity (AAV mice) maintained glucose homeostasis, lacked HCA/HCC, and were protected against age-related obesity and insulin resistance. Of the eleven rAAV-G6PC/rAAV-co-G6PC-treated G6PC-/- mice harboring 0.9-2.4% of normal hepatic G6Pase-α activity (AAV-low mice), 3 expressing 0.9-1.3% of normal hepatic G6Pase-α activity developed HCA/HCC, while 8 did not (AAV-low-NT). Finally, we showed that the AAV-low-NT mice exhibited a phenotype indistinguishable from that of AAV mice expressing ≥3% of normal hepatic G6Pase-α activity. The results establish the threshold of hepatic G6Pase-α activity required to prevent HCA/HCC and show that GSD-Ia mice harboring

  • 165. Liver-Directed Gene Therapy for Murine Glycogen Storage Disease Type IB
    Molecular Therapy, 2016
    Co-Authors: Joonhyun Kwon, Jun-ho Cho, Young Mok Lee, Goo-young Kim, Javier Anduaga, Janice Chou
    Abstract:

    Glycogen storage disease type Ib (GSD-Ib) deficient in the glucose-6-phosphate transporter (G6PT or SLC37A4) is characterized impaired glucose homeostasis, myeloid dysfunction, and long-term complication of hepatocellular adenoma (HCA). We have shown that gene therapy mediated by a recombinant (r) AAV8 vector expressing G6PT directed by the chicken β-actin promoter/CMV enhancer enabled the G6pt-/- mice lived to over 51 weeks but all 5 transduced G6pt-/- mice expressed only low levels of hepatic G6PT activity and two developed multiple HCAs with one undergoing malignant transformation. We now examined the safety and efficacy of rAAV8-GPE-G6PT, a rAAV8 vector expressing G6PT directed by the gluconeogenic tissue-specific human G6PC promoter/enhancer (GPE). Of the fifteen rAAV8-GPE-G6PT-treated G6pt-/- mice that lived over age 60 weeks expressed 2-62% of wild-type hepatic G6PT activity with only one developed HCA. The treated mice, including the HCA-bearing mouse exhibit a leaner phenotype along with normal blood metabolite, display normal glucose tolerance profiles, maintain normoglycemia over a 24-hour fast, and retain insulin sensitivity. We further show that activation of hepatic ChREBP signaling that improves glucose tolerance and insulin sensitivity is one mechanism that protects the rAAV-GPE-G6PT-treated G6pt-/- mice against age-related obesity and insulin resistance.

Fabienne Rajas - One of the best experts on this subject based on the ideXlab platform.

  • Glycogen storage disease type 1a is associated with disturbed vitamin A metabolism and elevated serum retinol levels
    Human Molecular Genetics, 2020
    Co-Authors: Ali Saeed, Janette Heegsma, Joanne Hoogerland, Hanna Wessel, Terry Derks, Eveline Van Der Veer, Gilles Mithieux, Fabienne Rajas, Maaike Oosterveer, Klaas Nico Faber
    Abstract:

    Glycogen storage disease type 1a (GSD Ia) is an inborn error of metabolism caused by mutations in the G6PC gene, encoding the catalytic subunit of glucose-6-phosphatase. Early symptoms include severe fasting intolerance, failure to thrive and hepatomegaly, biochemically associated with nonketotic hypoglycemia, fasting hyperlactidemia, hyperuricemia and hyperlipidemia. Dietary management is the cornerstone of treatment aiming at maintaining euglycemia, prevention of secondary metabolic perturbations and long-term complications, including liver (hepatocellular adenomas and carcinomas), kidney and bone disease (hypovitaminosis D and osteoporosis). As impaired vitamin A homeostasis also associates with similar symptoms and is coordinated by the liver, we here analysed whether vitamin A metabolism is affected in GSD Ia patients and liver-specific G6PC-/- knock-out mice. Serum levels of retinol and retinol binding protein 4 (RBP4) were significantly increased in both GSD Ia patients and L-G6PC-/- mice. In contrast, hepatic retinol levels were significantly reduced in L-G6PC-/- mice, while hepatic retinyl palmitate (vitamin A storage form) and RBP4 levels were not altered. Transcript and protein analyses indicate an enhanced production of retinol and reduced conversion the retinoic acids (unchanged LRAT, Pnpla2/ATGL and Pnpla3 up, Cyp26a1 down) in L-G6PC-/- mice. Aberrant expression of genes involved in vitamin A metabolism was associated with reduced basal messenger RNA levels of markers of inflammation (Cd68, Tnfα, Nos2, Il-6) and fibrosis (Col1a1, Acta2, Tgfβ, Timp1) in livers of L-G6PC-/- mice. In conclusion, GSD Ia is associated with elevated serum retinol and RBP4 levels, which may contribute to disease symptoms, including osteoporosis and hepatic steatosis.

  • The role of kidney in the inter-organ coordination of endogenous glucose production during fasting
    Molecular metabolism, 2018
    Co-Authors: Keizo Kaneko, Fabienne Rajas, Amandine Gautier-stein, Maud Soty, Carine Zitoun, Adeline Duchampt, Marine Silva, Erwann Philippe, Gilles Mithieux
    Abstract:

    OBJECTIVE: The respective contributions to endogenous glucose production (EGP) of the liver, kidney and intestine vary during fasting. We previously reported that the deficiency in either hepatic or intestinal gluconeogenesis modulates the repartition of EGP via glucagon secretion (humoral factor) and gut-brain-liver axis (neural factor), respectively. Considering renal gluconeogenesis reportedly accounted for approximately 50% of EGP during fasting, we examined whether a reduction in renal gluconeogenesis could promote alterations in the repartition of EGP in this situation. METHODS: We studied mice whose glucose-6-phosphatase (G6Pase) catalytic subunit (G6PC) is specifically knocked down in the kidneys (K-G6PC-/- mice) during fasting. We also examined the additional effects of intestinal G6PC deletion, renal denervation and vitamin D administration on the altered glucose metabolism in K-G6PC-/- mice. RESULTS: Compared with WT mice, K-G6PC-/- mice exhibited (1) lower glycemia, (2) enhanced intestinal but not hepatic G6Pase activity, (3) enhanced hepatic glucokinase (GK encoded by Gck) activity, (4) increased hepatic glucose-6-phosphate and (5) hepatic glycogen spared from exhaustion during fasting. Increased hepatic Gck expression in the post-absorptive state could be dependent on the enhancement of insulin signal (AKT phosphorylation) in K-G6PC-/- mice. In contrast, the increase in hepatic GK activity was not observed in mice with both kidney- and intestine-knockout (KI-G6PC-/- mice). Hepatic Gck gene expression and hepatic AKT phosphorylation were reduced in KI-G6PC-/- mice. Renal denervation by capsaicin did not induce any effect on glucose metabolism in K-G6PC-/- mice. Plasma level of 1,25 (OH)2 D3, an active form of vitamin D, was decreased in K-G6PC-/- mice. Interestingly, the administration of 1,25 (OH)2 D3 prevented the enhancement of intestinal gluconeogenesis and hepatic GK activity and blocked the accumulation of hepatic glycogen otherwise observed in K-G6PC-/- mice during fasting. CONCLUSIONS: A diminution in renal gluconeogenesis that is accompanied by a decrease in blood vitamin D promotes a novel repartition of EGP among glucose producing organs during fasting, featured by increased intestinal gluconeogenesis that leads to sparing glycogen stores in the liver. Our data suggest a possible involvement of a crosstalk between the kidneys and intestine (via the vitamin D system) and the intestine and liver (via a neural gut-brain axis), which might take place in the situations of deficient renal glucose production, such as chronic kidney disease.

  • The role of kidney in the inter-organ coordination of endogenous glucose production during fasting
    Elsevier, 2018
    Co-Authors: Keizo Kaneko, Fabienne Rajas, Amandine Gautier-stein, Maud Soty, Carine Zitoun, Adeline Duchampt, Marine Silva, Erwann Philippe, Gilles Mithieux
    Abstract:

    Objective: The respective contributions to endogenous glucose production (EGP) of the liver, kidney and intestine vary during fasting. We previously reported that the deficiency in either hepatic or intestinal gluconeogenesis modulates the repartition of EGP via glucagon secretion (humoral factor) and gut–brain–liver axis (neural factor), respectively. Considering renal gluconeogenesis reportedly accounted for approximately 50% of EGP during fasting, we examined whether a reduction in renal gluconeogenesis could promote alterations in the repartition of EGP in this situation. Methods: We studied mice whose glucose-6-phosphatase (G6Pase) catalytic subunit (G6PC) is specifically knocked down in the kidneys (K-G6PC-/- mice) during fasting. We also examined the additional effects of intestinal G6PC deletion, renal denervation and vitamin D administration on the altered glucose metabolism in K-G6PC-/- mice. Results: Compared with WT mice, K-G6PC-/- mice exhibited (1) lower glycemia, (2) enhanced intestinal but not hepatic G6Pase activity, (3) enhanced hepatic glucokinase (GK encoded by Gck) activity, (4) increased hepatic glucose-6-phosphate and (5) hepatic glycogen spared from exhaustion during fasting. Increased hepatic Gck expression in the post-absorptive state could be dependent on the enhancement of insulin signal (AKT phosphorylation) in K-G6PC-/- mice. In contrast, the increase in hepatic GK activity was not observed in mice with both kidney- and intestine-knockout (KI-G6PC-/- mice). Hepatic Gck gene expression and hepatic AKT phosphorylation were reduced in KI-G6PC-/- mice. Renal denervation by capsaicin did not induce any effect on glucose metabolism in K-G6PC-/- mice. Plasma level of 1,25 (OH)2 D3, an active form of vitamin D, was decreased in K-G6PC-/- mice. Interestingly, the administration of 1,25 (OH)2 D3 prevented the enhancement of intestinal gluconeogenesis and hepatic GK activity and blocked the accumulation of hepatic glycogen otherwise observed in K-G6PC-/- mice during fasting. Conclusions: A diminution in renal gluconeogenesis that is accompanied by a decrease in blood vitamin D promotes a novel repartition of EGP among glucose producing organs during fasting, featured by increased intestinal gluconeogenesis that leads to sparing glycogen stores in the liver. Our data suggest a possible involvement of a crosstalk between the kidneys and intestine (via the vitamin D system) and the intestine and liver (via a neural gut-brain axis), which might take place in the situations of deficient renal glucose production, such as chronic kidney disease. Keywords: Endogenous glucose production, Gluconeogenesis, Hypoglycemia, Glycogen, Chronic kidney disease, Vitamin

  • Clinical and biochemical heterogeneity between patients with glycogen storage disease type IA: the added value of CUSUM for metabolic control
    Journal of Inherited Metabolic Disease, 2017
    Co-Authors: Fabian Peeks, Fabienne Rajas, Maaike Oosterveer, Thomas Steunenberg, Foekje De Boer, M. Estela Rubio-gozalbo, Monique Williams, Rob Burghard, David Weinstein, Terry Derks
    Abstract:

    OBJECTIVE: To study heterogeneity between patients with glycogen storage disease type Ia (GSD Ia), a rare inherited disorder of carbohydrate metabolism caused by the deficiency of glucose-6-phosphatase (G6Pase). STUDY DESIGN: Descriptive retrospective study of longitudinal clinical and biochemical data and long-term complications in 20 GSD Ia patients. We included 11 patients with homozygous G6PC mutations and siblings from four families carrying identical G6PC genotypes. To display subtle variations for repeated triglyceride measurements with respect to time for individual patients, CUSUM-analysis graphs were constructed. RESULTS: Patients with different homozygous G6PC mutations showed important differences in height, BMI, and biochemical parameters (i.e., lactate, uric acid, triglyceride, and cholesterol concentrations). Furthermore, CUSUM-analysis predicts and displays subtle changes in longitudinal blood triglyceride concentrations. Siblings in families also displayed important differences in biochemical parameters (i.e., lactate, uric acid, triglycerides, and cholesterol concentrations) and long-term complications (i.e., liver adenomas, nephropathy, and osteopenia/osteoporosis). CONCLUSIONS: Differences between GSD Ia patients reflect large clinical and biochemical heterogeneity. Heterogeneity between GSD Ia patients with homozygous G6PC mutations indicate an important role of the G6PC genotype/mutations. Differences between affected siblings suggest an additional role (genetic and/or environmental) of modifying factors defining the GSD Ia phenotype. CUSUM-analysis can facilitate single-patient monitoring of metabolic control and future application of this method may improve precision medicine for patients both with GSD and remaining inherited metabolic diseases.

  • Lessons from new mouse models of glycogen storage disease type 1a in relation to the time course and organ specificity of the disease
    Journal of Inherited Metabolic Disease, 2015
    Co-Authors: Fabienne Rajas, Amandine Gautier-stein, Julie Clar, Gilles Mithieux
    Abstract:

    Patients with glycogen storage diseases type 1 (GSD1) suffer from life-threatening hypoglycaemia, when left untreated. Despite an intensive dietary treatment, patients develop severe complications, such as liver tumors and renal failure, with aging. Until now, the animal models available for studying the GSD1 did not survive after weaning. To gain further insights into the molecular mechanisms of the disease and to evaluate potential treatment strategies, we have recently developed novel mouse models in which the catalytic subunit of glucose-6 phosphatase (G6PC) is deleted in each glucose-producing organ specifically. For that, B6.G6PCex3lox/ex3lox mice were crossed with transgenic mice expressing a recombinase under the control of the serum albumin, the kidney androgen protein or the villin promoter, in order to obtain liver, kidney or intestine G6PC-/- mice, respectively. As opposed to total G6PC knockout mice, tissue-specific G6PC deficiency allows mice to maintain their blood glucose by inducing glucose production in the other gluconeogenic organs. Even though it is considered that glucose is produced mainly by the liver, liver G6PC-/- mice are perfectly viable and exhibit the same hepatic pathological features as GSD1 patients, including the late development of hepatocellular adenomas and carcinomas. Interestingly, renal G6PC-/- mice developed renal symptoms similar to the early human GSD1 nephropathy. This includes glycogen overload that leads to nephromegaly and morphological and functional alterations in the kidneys. Thus, our data suggest that renal G6Pase deficiency per se is sufficient to induce the renal pathology of GSD1. Therefore, these new mouse models should allow us to improve the strategies of treatment on both nutritional and pharmacological points of view.