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Pathogenesis of growth failure and partial reversal with gene therapy in murine and canine Glycogen Storage Disease type Ia

dc.contributor.author Brooks, Elizabeth Drake
dc.contributor.author Little, Dianne
dc.contributor.author Arumugam, Ramamani
dc.contributor.author Sun, Baodong
dc.contributor.author Curtis, Sarah
dc.contributor.author Demaster, Amanda
dc.contributor.author Maranzano, Michael
dc.contributor.author Jackson, Mark W
dc.contributor.author Kishnani, Priya
dc.contributor.author Freemark, Michael S
dc.contributor.author Koeberl, Dwight D
dc.date.accessioned 2018-06-29T15:13:36Z
dc.date.available 2018-06-29T15:13:36Z
dc.date.issued 2013
dc.identifier.issn 1096-7192
dc.identifier.uri https://hdl.handle.net/10161/17192
dc.description.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. © 2013 Elsevier Inc.
dc.publisher Elsevier BV
dc.relation.ispartof Molecular Genetics and Metabolism
dc.relation.isversionof 10.1016/j.ymgme.2013.03.018
dc.title Pathogenesis of growth failure and partial reversal with gene therapy in murine and canine Glycogen Storage Disease type Ia
dc.type Journal article
duke.contributor.id Little, Dianne|0461205
duke.contributor.id Sun, Baodong|0274636
duke.contributor.id Kishnani, Priya|0098965
duke.contributor.id Freemark, Michael S|0014165
duke.contributor.id Koeberl, Dwight D|0221062
dc.date.updated 2018-06-29T15:13:35Z
pubs.begin-page 161
pubs.end-page 170
pubs.issue 2
pubs.organisational-group School of Medicine
pubs.organisational-group Duke
pubs.organisational-group Duke Global Health Institute
pubs.organisational-group University Institutes and Centers
pubs.organisational-group Institutes and Provost's Academic Units
pubs.organisational-group Pediatrics, Endocrinology
pubs.organisational-group Pediatrics
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Sarah Stedman Nutrition & Metabolism Center
pubs.organisational-group Duke Molecular Physiology Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group Duke Clinical Research Institute
pubs.organisational-group Pediatrics, Medical Genetics
pubs.organisational-group Faculty
pubs.volume 109
duke.contributor.orcid Sun, Baodong|0000-0002-2191-0025


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