The upstream enhancer elements of the G6PC promoter are critical for optimal G6PC expression in murine glycogen storage disease type Ia.

Lee, Young Mok

Pan, Chi-Jiunn

Koeberl, Dwight D

Mansfield, Brian C

Chou, Janice Y

United States

2015-10-30T14:33:18Z

2013-11

Glycogen storage disease type-Ia (GSD-Ia) patients deficient in glucose-6-phosphatase-α (G6Pase-α or G6PC) manifest impaired glucose homeostasis characterized by fasting hypoglycemia, growth retardation, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, and lactic acidemia. Two efficacious recombinant adeno-associated virus pseudotype 2/8 (rAAV8) vectors expressing human G6Pase-α have been independently developed. One is a single-stranded vector containing a 2864-bp of the G6PC promoter/enhancer (rAAV8-GPE) and the other is a double-stranded vector containing a shorter 382-bp minimal G6PC promoter/enhancer (rAAV8-miGPE). To identify the best construct, a direct comparison of the rAAV8-GPE and the rAAV8-miGPE vectors was initiated to determine the best vector to take forward into clinical trials. We show that the rAAV8-GPE vector directed significantly higher levels of hepatic G6Pase-α expression, achieved greater reduction in hepatic glycogen accumulation, and led to a better toleration of fasting in GSD-Ia mice than the rAAV8-miGPE vector. Our results indicated that additional control elements in the rAAV8-GPE vector outweigh the gains from the double-stranded rAAV8-miGPE transduction efficiency, and that the rAAV8-GPE vector is the current choice for clinical translation in human GSD-Ia.

http://www.ncbi.nlm.nih.gov/pubmed/23856420

S1096-7192(13)00216-3

1096-7206

https://hdl.handle.net/10161/10803

eng

Elsevier BV

Mol Genet Metab

10.1016/j.ymgme.2013.06.014

AAV

Adeno-associated virus

G6P

G6PC promoter/enhancer

G6Pase

GPE

GSD-Ia

Gene therapy

Glucose-6-phosphatase

Glycogen storage disease type I

HCA

adeno-associated virus

glucose-6-phosphatase

glucose-6-phosphate

glycogen storage disease type Ia

hepatocellular adenoma

Animals

Dependovirus

Disease Models, Animal

Enhancer Elements, Genetic

Gene Expression

Gene Expression Regulation

Genetic Therapy

Genetic Vectors

Glucose

Glucose-6-Phosphatase

Glycogen Storage Disease Type I

Humans

Liver

Metabolome

Mice

Mice, Knockout

Organ Specificity

Promoter Regions, Genetic

Transduction, Genetic

Transgenes

The upstream enhancer elements of the G6PC promoter are critical for optimal G6PC expression in murine glycogen storage disease type Ia.

Journal article

http://www.ncbi.nlm.nih.gov/pubmed/23856420

275

280

3

Basic Science Departments

Clinical Science Departments

Duke

Molecular Genetics and Microbiology

Pediatrics

Pediatrics, Medical Genetics

School of Medicine

Published

110