Antibody-Mediated Enzyme Therapeutics and Applications in Glycogen Storage Diseases.
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ABSTRACT:
SUBMITTER: Zhou Z
PROVIDER: S-EPMC6889062 | biostudies-literature | 2019 Dec
REPOSITORIES: biostudies-literature
Publications
Antibody-Mediated Enzyme Therapeutics and Applications in Glycogen Storage Diseases.
Zhou Zhengqiu Z Austin Grant L GL Shaffer Robert R Armstrong Dustin D DD Gentry Matthew S MS
Trends in molecular medicine 20190912 12
The use of antibodies as targeting molecules or cell-penetrating tools has emerged at the forefront of pharmaceutical research. Antibody-directed therapies in the form of antibody-drug conjugates, immune modulators, and antibody-directed enzyme prodrugs have been most extensively utilized as hematological, rheumatological, and oncological therapies, but recent developments are identifying additional applications of antibody-mediated delivery systems. A novel application of this technology is for ...[more]
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Project description: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.
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Project description:The focus of this review is the development of gene therapy for glycogen storage diseases (GSDs). GSD results from the deficiency of specific enzymes involved in the storage and retrieval of glucose in the body. Broadly, GSDs can be divided into types that affect liver or muscle or both tissues. For example, glucose-6-phosphatase (G6Pase) deficiency in GSD type Ia (GSD Ia) affects primarily the liver and kidney, while acid ?-glucosidase (GAA) deficiency in GSD II causes primarily muscle disease. The lack of specific therapy for the GSDs has driven efforts to develop new therapies for these conditions. Gene therapy needs to replace deficient enzymes in target tissues, which has guided the planning of gene therapy experiments. Gene therapy with adeno-associated virus (AAV) vectors has demonstrated appropriate tropism for target tissues, including the liver, heart and skeletal muscle in animal models for GSD. AAV vectors transduced liver and kidney in GSD Ia and striated muscle in GSD II mice to replace the deficient enzyme in each disease. Gene therapy has been advanced to early phase clinical trials for the replacement of G6Pase in GSD Ia and GAA in GSD II (Pompe disease). Other GSDs have been treated in proof-of-concept studies, including GSD III, IV and V. The future of gene therapy appears promising for the GSDs, promising to provide more efficacious therapy for these disorders in the foreseeable future.
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Project description:INTRODUCTION:The gut microbiome has been related to several features present in Glycogen Storage Diseases (GSD) patients including obesity, inflammatory bowel disease (IBD) and liver disease. OBJECTIVES:The primary objective of this study was to investigate associations between GSD and the gut microbiota. METHODS:Twenty-four GSD patients on treatment with uncooked cornstarch (UCCS), and 16 healthy controls had their faecal microbiota evaluated through 16S rRNA gene sequencing. Patients and controls were ≥3 years of age and not on antibiotics. Faecal pH, calprotectin, mean daily nutrient intake and current medications were recorded and correlated with gut microbiome. RESULTS:Patients' group presented higher intake of UCCS, higher prevalence of IBD (n = 04/24) and obesity/overweight (n = 18/24) compared to controls (n = 0 and 06/16, respectively). Both groups differed regarding diet (in patients, the calories' source was mainly the UCSS, and the intake of fat, calcium, sodium, and vitamins was lower than in controls), use of angiotensin-converting enzyme inhibitors (patients = 11, controls = 0; p-value = 0.001) multivitamins (patients = 22, controls = 01; p-value = 0.001), and mean faecal pH (patients = 6.23; controls = 7.41; p = 0.001). The GSD microbiome was characterized by low diversity and distinct microbial structure. The operational taxonomic unit (OTU) abundance was significantly influenced by faecal pH (r = 0.77; p = 6.8e-09), total carbohydrate (r = -0.6; p = 4.8e-05) and sugar (r = 0.057; p = 0.00013) intakes. CONCLUSIONS:GSD patients presented intestinal dysbiosis, showing low faecal microbial diversity in comparison with healthy controls. Those findings might be due to the disease per se, and/or to the different diets, use of UCSS and of medicines, and obesity rate found in patients. Although the main driver of these differences is unknown, this study might help to understand how the nutritional management affects GSD patients.
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