Pathogenesis of growth failure and partial reversal with gene therapy in murine and canine Glycogen Storage Disease type Ia
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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. © 2013 Elsevier Inc.
Published Version (Please cite this version)10.1016/j.ymgme.2013.03.018
Publication InfoArumugam, Ramamani; Brooks, ED; Curtis, S; DeMaster, A; Freemark, Michael Scott; Jackson, MW; ... Sun, Baodong (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 http://hdl.handle.net/10161/13933.
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Robert C. Atkins, M.D. and Veronica Atkins Professor of Pediatrics, in the School of Medicine
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. In recent studies we have 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
Chen Family Professor of Pediatrics
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 2) The development of new therapies for genetic disorders through translational research 3) The development and execution of large multicenter trials to confirm safety and efficacy of potential th
Professor of Pediatrics
The focus of our research has been the development of gene therapy with adeno-associated virus (AAV) vectors, most recently by genome editing with CRISPR/Cas9. We have developed gene therapy for inherited disorders of metabolism, especially glycogen storage disease (GSD) and phenylketonuria (PKU). 1) GSD type Ia: Glucose-6-phosphatase (G6Pase) deficient animals provide models for developing new therapy for GSD type Ia, although early mortality complicates research with both
Assistant Professor in Orthopaedic Surgery
BVSc (DVM Equivalent) University of Liverpool 1998MSpVM North Carolina State University 2003PhD (Physiology and Biotechnology) North Carolina State University 2006Diplomate, American College of Veterinary Surgeons 2004My research focus is rotator cuff tendon tissue engineering and tendon-bone interfacial regeneration using a novel electrospinning technology. I have also developed an interest in integrated 'omics to assess continued risk for tendon degeneration
Associate Professor of Pediatrics
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 studie
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