Pathogenesis of growth failure and partial reversal with gene therapy in murine and canine Glycogen Storage Disease type Ia.
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2013-06
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Abstract
Glycogen Storage Disease type Ia (GSD-Ia) in humans frequently causes delayed bone maturation, decrease in final adult height, and decreased growth velocity. This study evaluates the pathogenesis of growth failure and the effect of gene therapy on growth in GSD-Ia affected dogs and mice. Here we found that homozygous G6pase (-/-) mice with GSD-Ia have normal growth hormone (GH) levels in response to hypoglycemia, decreased insulin-like growth factor (IGF) 1 levels, and attenuated weight gain following administration of GH. Expression of hepatic GH receptor and IGF 1 mRNAs and hepatic STAT5 (phospho Y694) protein levels are reduced prior to and after GH administration, indicating GH resistance. However, restoration of G6Pase expression in the liver by treatment with adeno-associated virus 8 pseudotyped vector expressing G6Pase (AAV2/8-G6Pase) corrected body weight, but failed to normalize plasma IGF 1 in G6pase (-/-) mice. Untreated G6pase (-/-) mice also demonstrated severe delay of growth plate ossification at 12 days of age; those treated with AAV2/8-G6Pase at 14 days of age demonstrated skeletal dysplasia and limb shortening when analyzed radiographically at 6 months of age, in spite of apparent metabolic correction. Moreover, gene therapy with AAV2/9-G6Pase only partially corrected growth in GSD-Ia affected dogs as detected by weight and bone measurements and serum IGF 1 concentrations were persistently low in treated dogs. We also found that heterozygous GSD-Ia carrier dogs had decreased serum IGF 1, adult body weights and bone dimensions compared to wild-type littermates. In sum, these findings suggest that growth failure in GSD-Ia results, at least in part, from hepatic GH resistance. In addition, gene therapy improved growth in addition to promoting long-term survival in dogs and mice with GSD-Ia.
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Brooks, Elizabeth Drake, Dianne Little, Ramamani Arumugam, Baodong Sun, Sarah Curtis, Amanda Demaster, Michael Maranzano, Mark W Jackson, et al. (2013). Pathogenesis of growth failure and partial reversal with gene therapy in murine and canine Glycogen Storage Disease type Ia. Molecular Genetics and Metabolism, 109(2). pp. 161–170. 10.1016/j.ymgme.2013.03.018 Retrieved from https://hdl.handle.net/10161/15086.
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Scholars@Duke
Baodong Sun
My overall research interests are finding effective treatment for human glycogen storage diseases (GSDs) and other inherited metabolic disorders. My current research focuses on identification of novel therapeutic targets and development of effective therapies for GSD II (Pompe disease), GSD III (Cori disease), and GSD IV (Andersen disease) using cellular and animal disease models. The main therapeutic approaches we are using in our pre-clinical studies include protein/enzyme therapy, AAV-mediated gene therapy, and substrate reduction therapy with small molecule drugs.
Priya Sunil Kishnani
RESEARCH INTERESTS
A multidisciplinary approach to care of individuals with genetic disorders in conjunction with clinical and bench research that contributes to:
1) An understanding of the natural history and delineation of long term complications of genetic disorders with a special focus on liver Glycogen storage disorders, lysosomal disorders with a special focus on Pompe disease, Down syndrome and hypophosphatasia
2) ) The development of new therapies such as AAV gene therapy, enzyme therapy, small molecule and other approaches for genetic disorders through translational research
3) The development and execution of large multicenter trials to confirm safety and efficacy of potential therapies
4) Role of antibodies/immune response in patients on therapeutic proteins and AAV gene therapy
. Glycogen Storage Disease (GSD): We are actively following subjects with all types of Glycogen Storage Disease, with particular emphasis on types I, II, III, IV, VI and IX. The goal of the treatment team is to better determine the clinical phenotype and long term complications of these diseases. Attention to disease manifestations observed in adulthood, such as adenomas and risk for HCC, is of paramount importance in monitoring and treating these chronic illnesses. We are establishing clinical algorithms for managing adenomas, and the overall management of these patients including cardiac, bone, muscle and liver issues. A special focus is biomarker discovery, an Omics approach including metabolomics and immune phenotyping. We are working on AAV gene therapy for several hepatic GSDs
.Lysosomal Storage Disease: The Duke Lysosomal Storage Disease (LSD) treatment center follows and treats patients with Pompe, Gaucher, Fabry, Mucopolysaccharidosis, Niemann Pick, LAL-D and other LSD's. The Duke Metabolism Clinical Research Team is exploring many aspects of enzyme replacement therapy (ERT), including impact on different systems, differential response, and long term effects. Other symptomatic and treatment interventions for this category of diseases are also being explored in the context of clinical care.
. Pompe Disease: The care team has extensive experience in the care of infants and adults with Pompe disease and was instrumental in conducting clinical trials and the bench to bedside work that led to the 2006 FDA approval of alglucosidase alfa, the first treatment for this devastating disease. We are currently focusing on role of antibodies/immune response on patient outcome and role of immune modulation/immune suppression as an adjunct to ERT. Our team is also working on AAV gene therapy for Pompe disease. A focus is on newborn screening (NBS) and understanding the clinical phenotype and management approaches for babies identified via NBS
. Hypophosphatasia: We follow a large cohort of patients with HPP. The goal is to understand the features of the disease beyond bone disease, development of biomarkers, role of ERT and immune responses in HPP
. Neuromuscular disorders: We are collaborating with neurologists, cardiologists and neuromuscular physicians to serve as a treatment site for clinical trials in these diseases. We are currently involved in trials of DMD and are working closely on setting up collaborations for studies in SMA.
Michael Scott Freemark
The primary objective of my basic research has been to elucidate the roles of placental and fetal hormones in the regulation of maternal metabolism and fetal growth. My work has focused on the lactogenic hormones produced by the pituitary gland and placenta. To that end we used targeted knockout mice to explore the molecular mechanisms by which prolactin and placental lactogen regulate pancreatic beta cell mass and insulin production during pregnancy and postnatal life.
I also have a longstanding clinical research interest in the pathogenesis and treatment of obesity and hyperlipidemia and the prevention of type 2 diabetes. In previous studies we showed that the drug metformin reduces fat stores and blood glucose and insulin levels in obese adolescents and may reduce the risk of progression to diabetes in selected patients. We have also examined the unique metabolic characteristics of Prader Willi syndrome, a genetic obesity disorder.
Finally, my colleagues and I have performed detailed studies of hormone production and intermediary metabolism in malnourished children in Uganda, Bangladesh, Liberia, and Burkina Faso and characterized the effects of concurrent HIV infection on nutritional recovery. We showed that the adipocyte hormone leptin is a major determinant of morbidity and mortality in children with moderate and severe acute malnutrition.
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