scholarly journals mRNA therapy restores euglycemia and prevents liver tumors in murine model of glycogen storage disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jingsong Cao ◽  
Minjung Choi ◽  
Eleonora Guadagnin ◽  
Maud Soty ◽  
Marine Silva ◽  
...  
Keyword(s):  
Glycogen Storage Disease ◽  
Murine Model ◽  
Storage Disease ◽  
Liver Tumors ◽  
Glycogen Storage ◽  
Human Condition ◽  
Efficacy And Safety ◽  
Current Standard ◽  
Enzyme Replacement ◽  
Life Threatening

AbstractGlycogen Storage Disease 1a (GSD1a) is a rare, inherited metabolic disorder caused by deficiency of glucose 6-phosphatase (G6Pase-α). G6Pase-α is critical for maintaining interprandial euglycemia. GSD1a patients exhibit life-threatening hypoglycemia and long-term liver complications including hepatocellular adenomas (HCAs) and carcinomas (HCCs). There is no treatment for GSD1a and the current standard-of-care for managing hypoglycemia (Glycosade®/modified cornstarch) fails to prevent HCA/HCC risk. Therapeutic modalities such as enzyme replacement therapy and gene therapy are not ideal options for patients due to challenges in drug-delivery, efficacy, and safety. To develop a new treatment for GSD1a capable of addressing both the life-threatening hypoglycemia and HCA/HCC risk, we encapsulated engineered mRNAs encoding human G6Pase-α in lipid nanoparticles. We demonstrate the efficacy and safety of our approach in a preclinical murine model that phenotypically resembles the human condition, thus presenting a potential therapy that could have a significant therapeutic impact on the treatment of GSD1a.

scholarly journals Circulating exosomal microRNAs as potential biomarkers of hepatic injury and inflammation in a murine model of glycogen storage disease type 1a

2020 ◽  
Vol 13 (9) ◽  
pp. dmm043364
Author(s):  
Roberta Resaz ◽  
Davide Cangelosi ◽  
Martina Morini ◽  
Daniela Segalerba ◽  
Luca Mastracci ◽  
...  
Keyword(s):  
Glycogen Storage Disease ◽  
Murine Model ◽  
Storage Disease ◽  
Hepatocellular Adenoma ◽  
Glycogen Storage Disease Type ◽  
Glycogen Storage ◽  
Disease Type ◽  
Telomere Maintenance ◽  
Differentially Expressed ◽  
Potential Biomarkers

ABSTRACTMost patients affected by glycogen storage disease type 1a (GSD1a), an inherited metabolic disorder caused by mutations in the enzyme glucose-6-phosphatase-α (G6Pase-α), develop renal and liver complications, including the development of hepatocellular adenoma/carcinoma. The purpose of this study was to identify potential biomarkers of the pathophysiology of the GSD1a-affected liver. To this end, we used the plasma exosomes of a murine model of GSD1a, the LS-G6pc−/− mouse, to uncover the modulation in microRNA expression associated with the disease. The microRNAs differentially expressed between LS-G6pc−/− and wild-type mice, LS-G6pc−/− mice with hepatocellular adenoma and LS-G6pc−/− mice without adenoma, and LS-G6pc−/− mice with amyloidosis and LS-G6pc−/− mice without amyloidosis were identified. Pathway analysis demonstrated that the target genes of the differentially expressed microRNA were significantly enriched for the insulin signaling pathway, glucose and lipid metabolism, Wnt/β-catenin, telomere maintenance and hepatocellular carcinoma, and chemokine and immune regulation signaling pathways. Although some microRNAs were common to the different pathologic conditions, others were unique to the cancerous or inflammatory status of the animals. Therefore, the altered expression of several microRNAs is correlated with various pathologic liver states and might help to distinguish them during the progression of the disease and the development of late GSD1a-associated complications.

Enzyme replacement therapy in severe adult-onset glycogen storage disease type II

2008 ◽  
Vol 25 (8) ◽  
pp. 820-829 ◽  
Author(s):  
Sabrina Ravaglia ◽  
Cesare Danesino ◽  
Anna Pichiecchio ◽  
Alessandra Repetto ◽  
Guy Umberto Poloni ◽  
...  
Keyword(s):  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Glycogen Storage Disease ◽  
Storage Disease ◽  
Glycogen Storage Disease Type ◽  
Glycogen Storage ◽  
Disease Type ◽  
Type Ii ◽  
Adult Onset ◽  
Enzyme Replacement

scholarly journals Late-Onset Glycogen Storage Disease Type II (Pompe’s Disease) with a Novel Mutation: A Malaysian Experience

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Hiew Fu Liong ◽  
Siti Aishah Abdul Wahab ◽  
Yusnita Yakob ◽  
Ngu Lock Hock ◽  
Wong Kum Thong ◽  
...  
Keyword(s):  
Glycogen Storage Disease ◽  
Storage Disease ◽  
Late Onset ◽  
Novel Mutation ◽  
High Protein Diet ◽  
Glycogen Storage Disease Type ◽  
Glycogen Storage ◽  
Enzyme Replacement ◽  
Pompe’S Disease ◽  
Pompe's Disease

Pompe’s disease (acid maltase deficiency, glycogen storage disease type II) is an autosomal recessive disorder caused by a deficiency of lysosomal acidα-1,4-glucosidase, resulting in excessive accumulation of glycogen in the lysosomes and cytoplasm of all tissues, most notably in skeletal muscles. We present a case of adult-onset Pompe’s disease with progressive proximal muscles weakness over 5 years and respiratory failure on admission, requiring prolonged mechanical ventilation. Electromyography showed evidence of myopathic process with small amplitudes, polyphasic motor unit action potentials, and presence of pseudomyotonic discharges. Muscle biopsy showed glycogen-containing vacuoles in the muscle fibers consistent with glycogen storage disease. Genetic analysis revealed two compound heterozygous mutations at c.444C>G (p.Tyr148*) in exon 2 and c.2238G>C (p.Trp746Cys) in exon 16, with the former being a novel mutation. This mutation has not been reported before, to our knowledge. The patient was treated with high protein diet during the admission and subsequently showed good clinical response to enzyme replacement therapy with survival now to the eighth year.Conclusion. In patients with late-onset adult Pompe’s disease, careful evaluation and early identification of the disease and its treatment with high protein diet and enzyme replacement therapy improve muscle function and have beneficial impact on long term survival.

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