Gene therapy for Glut1-deficient mouse using an adeno-associated virus vector with the human intrinsic GLUT1 promoter

被引：20

作者：

Nakamura, Sachie ^{[1
]}

Muramatsu, Shin-ichi ^{[2
,7
]}

Takino, Naomi ^{[2
]}

Ito, Mika ^{[2
]}

Jimbo, Eriko F. ^{[1
]}

Shimazaki, Kuniko ^{[3
]}

Onaka, Tatsushi ^{[4
]}

Ohtsuki, Sumio ^{[5
]}

Terasaki, Tetsuya ^{[6
]}

Yamagata, Takanori ^{[1
]}

Osaka, Hitoshi ^{[1
]}

机构：

[1] Jichi Med Univ, Dept Pediat, Shimotsuke, Tochigi, Japan

[2] Jichi Med Univ, Div Neurol, Shimotsuke, Tochigi, Japan

[3] Jichi Med Univ, Dept Neurosurg, Shimotsuke, Tochigi, Japan

[4] Jichi Med Univ, Dept Physiol, Div Brain & Neurophysiol, Shimotsuke, Tochigi, Japan

[5] Kumamoto Univ, Dept Pharmaceut Microbiol, Fac Life Sci, Kumamoto, Japan

[6] Tohoku Univ, Grad Sch Pharmaceut Sci, Div Membrane Transport & Drug Targeting, Sendai, Miyagi, Japan

[7] Univ Tokyo, Inst Med Sci, Ctr Gene & Cell Therapy, Tokyo, Japan

来源：

JOURNAL OF GENE MEDICINE | 2018年 / 20卷 / 04期

基金：

日本学术振兴会;

关键词：

adeno-associated virus (AAV); gene therapy; glucose transporter 1 deficiency syndrome (GLUT1DS); GLUT1; SLC2A1; GLUCOSE-TRANSPORTER-1 DEFICIENCY SYNDROME; GLUCOSE-TRANSPORTER PROTEINS; NATIONWIDE SURVEY; KETOGENIC DIET; BRAIN; DELIVERY; MODEL; EXPRESSION; NEURONS; HYPEROSMOLARITY;

D O I：

10.1002/jgm.3013

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

BackgroundWe generated an adeno-associated virus (AAV) vector in which the human SLC2A1 gene, encoding glucose transporter type 1 (GLUT1), was expressed under the human endogenous GLUT1 promoter (AAV-GLUT1). We examined whether AAV-GLUT1 administration could lead to functional improvement in GLUT1-deficient mice. MethodsWe extrapolated human endogenous GLUT1 promoter sequences from rat minimal Glut1 promoter sequences. We generated a tyrosine-mutant AAV9/3 vector in which human SLC2A1-myc-DDK was expressed under the human GLUT1 promoter (AAV-GLUT1). AAV-GLUT1 was administered to GLUT1-deficient mice (GLUT1(+/-) mice) via intracerebroventricular injection (1.85 x 10(10) vg/mouse or 6.5 x 10(10) vg/mouse). We analyzed exogenous GLUT1 mRNA and protein expression in the brain and other major organs. We also examined improvements of cerebral microvasculature, motor function using rota-rod and footprint tests, as well as blood and cerebrospinal fluid (CSF) glucose levels. Additionally, we confirmed exogenous GLUT1 protein distribution in the brain and other organs after intracardiac injection (7.8 x 10(11) vg/mouse). ResultsExogenous GLUT1 protein was strongly expressed in the cerebral cortex, hippocampus and thalamus. It was mainly expressed in endothelial cells, and partially expressed in neural cells and oligodendrocytes. Motor function and CSF glucose levels were significantly improved following intracerebroventricular injection. Exogenous GLUT1 expression was not detected in other organs after intracerebroventricular injection of AAV-GLUT1, whereas it was detected in the liver and muscle tissue after intracardiac injection. ConclusionsExogenous GLUT1 expression after AAV-GLUT1 injection approximated that of physiological human GLUT1 expression. Local central nervous system administration of AAV-GLUT1 improved CSF glucose levels and motor function of GLUT1-deficient mice and minimized off-target effects.

引用

页数：15

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