bims-glecem 2023-07-23 papers

Issue of 2023–07–23
five papers selected by
Dipsikha Biswas, Københavns Universitet

World J Gastroenterol. 2023 Jul 07. 29(25): 3932-3963

Glycogen storage diseases (GSDs), also referred to as glycogenoses, are inherited metabolic disorders of glycogen metabolism caused by deficiency of enzymes or transporters involved in the synthesis or degradation of glycogen leading to aberrant storage and/or utilization. The overall estimated GSD incidence is 1 case per 20000-43000 live births. There are over 20 types of GSD including the subtypes. This heterogeneous group of rare diseases represents inborn errors of carbohydrate metabolism and are classified based on the deficient enzyme and affected tissues. GSDs primarily affect liver or muscle or both as glycogen is particularly abundant in these tissues. However, besides liver and skeletal muscle, depending on the affected enzyme and its expression in various tissues, multiorgan involvement including heart, kidney and/or brain may be seen. Although GSDs share similar clinical features to some extent, there is a wide spectrum of clinical phenotypes. Currently, the goal of treatment is to maintain glucose homeostasis by dietary management and the use of uncooked cornstarch. In addition to nutritional interventions, pharmacological treatment, physical and supportive therapies, enzyme replacement therapy (ERT) and organ transplantation are other treatment approaches for both disease manifestations and long-term complications. The lack of a specific therapy for GSDs has prompted efforts to develop new treatment strategies like gene therapy. Since early diagnosis and aggressive treatment are related to better prognosis, physicians should be aware of these conditions and include GSDs in the differential diagnosis of patients with relevant manifestations including fasting hypoglycemia, hepatomegaly, hypertransaminasemia, hyperlipidemia, exercise intolerance, muscle cramps/pain, rhabdomyolysis, and muscle weakness. Here, we aim to provide a comprehensive review of GSDs. This review provides general characteristics of all types of GSDs with a focus on those with liver involvement.

Keywords: Glycogen storage disease; Hypoglycemia; Liver; Muscle

DOI: https://doi.org/10.3748/wjg.v29.i25.3932

J Inherit Metab Dis. 2023 Jul 19.

CRISPR/Cas9-based double strand oligonucleotide insertion strategy corrects metabolic abnormalities in murine glycogen storage disease type Ia.

Ananya Samanta, Nelson George, Irina Arnaoutova, Hung-Dar Chen, Brian C Mansfield, Christopher Hart, Troy Carlo, Janice Y Chou.

Glycogen storage disease type-Ia (GSD-Ia), characterized by impaired blood glucose homeostasis, is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC). Using the G6pc-R83C mouse model of GSD-Ia, we explored a CRISPR/Cas9-based double-strand DNA oligonucleotide (dsODN) insertional strategy that uses the non-homologous end joining repair mechanism to correct the pathogenic p.R83C variant in G6pc exon-2. The strategy is based on the insertion of a short dsODN into G6pc exon-2 to disrupt the native exon, and to introduce an additional splice acceptor site and the correcting sequence. When transcribed and spliced the edited gene would generate a wild-type mRNA encoding the native G6Pase-α protein. The editing reagents formulated in lipid nanoparticles (LNP) were delivered to the liver. Mice were treated either with one dose of LNP-dsODN at age 4 weeks or with 2 doses of LNP-dsODN at age 2 and 4 weeks. The G6pc-R83C mice receiving successful editing expressed ~4% of normal hepatic G6Pase-α activity, maintained glucose homeostasis, lacked hypoglycemic seizures, and displayed normalized blood metabolite profile. The outcomes are consistent with preclinical studies supporting previous gene augmentation therapy which is currently in clinical trials. This editing strategy may offer the basis for a therapeutic approach with an earlier clinical intervention than gene augmentation, with the additional benefit of a potentially permanent correction of the GSD-Ia phenotype. This article is protected by copyright. All rights reserved.

Keywords: Glucose-6-phosphatase-α; genome editing; glycogen storage disease type Ia mouse model; lipid nanoparticles; non-homologous end joining

DOI: https://doi.org/10.1002/jimd.12660

JCI Insight. 2023 Jul 18. pii: e170199. [Epub ahead of print]

AAV-mediated delivery of secreted acid α-glucosidase with enhanced uptake corrects neuromuscular pathology in Pompe mice.

Naresh K Meena, Davide Randazzo, Nina Raben, Rosa Puertollano.

Gene therapy is under advanced clinical development for several lysosomal storage disorders. Pompe disease, a debilitating neuromuscular illness that affects infants, children, and adults with different degrees of severity, is caused by a deficiency of lysosomal glycogen-degrading enzyme acid alpha-glucosidase (GAA). Here, we demonstrated that adeno-associated virus (AAV9)-mediated systemic gene transfer fully reversed glycogen storage in all key therapeutic targets - skeletal and cardiac muscles, the diaphragm, and the central nervous system (CNS) - in both young and severely affected old Gaa knockout mice. Furthermore, the therapy reversed secondary cellular abnormalities in skeletal muscle, such as autophagy and mTORC1/AMPK signaling. We used a newly developed AAV9 vector encoding a chimeric human GAA protein with enhanced uptake and secretion to facilitate efficient spread of the expressed protein among multiple target tissues. These results lay the groundwork for future clinical development strategy in Pompe disease.

Keywords: Autophagy; Gene therapy; Muscle Biology; Skeletal muscle

DOI: https://doi.org/10.1172/jci.insight.170199

Mol Metab. 2023 Jul 17. pii: S2212-8778(23)00113-8. [Epub ahead of print] 101779

Pregnane X receptor activation remodels glucose metabolism to promote NAFLD development in obese mice.

Mikko Karpale, Outi Kummu, Olli Kärkkäinen, Marko Lehtonen, Juha Näpänkangas, Uta M Herfurth, Albert Braeuning, Jaana Rysä, Jukka Hakkola.

OBJECTIVE: Both obesity and exposure to chemicals may induce non-alcoholic fatty liver disease (NAFLD). Pregnane X Receptor (PXR) is a central target of metabolism disrupting chemicals and disturbs hepatic glucose and lipid metabolism. We hypothesized that the metabolic consequences of PXR activation may be modified by existing obesity and associated metabolic dysfunction.
METHODS: Wildtype and PXR knockout male mice were fed high-fat diet to induce obesity and metabolic dysfunction. PXR was activated with pregnenolone-16α-carbonitrile. Glucose metabolism, hepatosteatosis, insulin signaling, glucose uptake, liver glycogen, plasma and liver metabolomics, and liver, white adipose tissue, and muscle transcriptomics were investigated.
RESULTS: PXR activation aggravated obesity-induced liver steatosis by promoting lipogenesis and inhibiting fatty acid disposal. Accordingly, hepatic insulin sensitivity was impaired and circulating alanine aminotransferase level increased. Lipid synthesis was facilitated by increased liver glucose uptake and utilization of glycogen reserves resulting in dissociation of hepatosteatosis and hepatic insulin resistance from the systemic glucose tolerance and insulin sensitivity. Furthermore, glucagon-induced hepatic glucose production was impaired. PXR deficiency did not protect from the metabolic manifestations of obesity, but the liver transcriptomics and metabolomics profiling suggest diminished activation of inflammation and less prominent changes in the overall metabolite profile.
CONCLUSIONS: Obesity and PXR activation by chemical exposure have a synergistic effect on NAFLD development. To support liver fat accumulation the PXR activation reorganizes glucose metabolism that seemingly improves systemic glucose metabolism. This implies that obese individuals, already predisposed to metabolic diseases, may be more susceptible to harmful metabolic effects of PXR-activating drugs and environmental chemicals.

Keywords: PXR; endocrine disrupting chemicals; glycogen; insulin resistance; steatosis

DOI: https://doi.org/10.1016/j.molmet.2023.101779

Mol Genet Metab. 2023 Jul 11. pii: S1096-7192(23)00280-9. [Epub ahead of print]139(4): 107650

Motor outcomes in patients with infantile and juvenile Pompe disease: Lessons from neurophysiological findings.

Anaïs Brassier, Samia Pichard, Manuel Schiff, Juliette Bouchereau, Claire-Marine Bérat, Catherine Caillaud, Aude Pion, Diala Khraiche, Brigitte Fauroux, Mehdi Oualha, Christine Barnerias, Isabelle Desguerre, Marie Hully, Marion Maquet, Elodie Deladrière, Pascale de Lonlay, Cyril Gitiaux.

In Infantile Onset Pompe Disease (IOPD), enzyme replacement therapy (ERT) may improve survival, cardiac function, and motor development. However, even with early enzyme replacement therapy, some patients experienced poor response to ERT and abnormal motor milestones that could be due to motor neuron involvement. In this long-term retrospective study, we analyzed concomitant clinical motor outcomes and electroneuromyography (ENMG) findings in patients with IOPD and Juvenile Onset Pompe Disease (JOPD). Twenty-nine pediatric patients were included and 20 surviving were analyzed for neuromotor studies: 12 had IOPD (group 1), 4 had JOPD (group 2) and 4 (group 3) received ERT in the first month of age. Motor nerve conduction studies were mostly normal. Needle EMG performed at diagnosis always indicated the existence of myopathy that responded to ERT. Two IOPD patients (group 1) presenting with mixed motor neuropathy and myopathy displayed a poor outcome and never walked. Two patients became non-walkers (one IOPD patient and one patient of group 3) at respectively 9 and 3 years of age. One JOPD patient is about to lose walking ability. This motor deterioration was associated with the development of a motor neuropathy. Patients older than 10 years of age develop a motor neuropathy. Initial or secondary motor neuron involvement seems to be associated with a poor motor outcome showing that ERT may fail to prevent the accumulation of glycogen in motor neuron. Neurophysiological findings are important to assess severity of motor neuron damage in all Pompe pediatric patients and should be systematically performed.

Keywords: Enzyme replacement therapy; Infantile onset Pompe disease; Juvenile onset Pompe disease; Lysosomal storage disease; Motor neuron involvement; Myopathic phenotype

DOI: https://doi.org/10.1016/j.ymgme.2023.107650