Gene therapy for a mouse model of glucose transporter-1 deficiency syndrome using AAV vector

2018 Fiscal Year Final Research Report

• Project/Area Number: 17H07057
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Pediatrics
• Research Institution: Jichi Medical University
• Principal Investigator: Nakamura Sachie 自治医科大学, 医学部, 助教 (20382955)
• Project Period (FY): 2017-08-25 – 2019-03-31
• Keywords: 遺伝子治療 / グルコーストランスポーター1欠損症 / AAV / GLUT1 / SLC2A1

Outline of Final Research Achievements

We 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 if AAV-GLUT1 administration could lead to functional improvement in GLUT1-deficient mice.
AAV-GLUT1 was administered to GLUT1+/- mice via intra-cerebroventricular injection. Additionally, we confirmed that exogenous GLUT1 protein was distributed in the brain and other organs after intra-cardiac injection of AAV-GLUT1.After AAV-GLUT1 injection, exogenous GLUT1 protein was mainly expressed in endothelial cells, and partially expressed in neural cells and oligodendrocytes. It was transduced in the cerebral cortex, hippocampus, and thalamus, and the expression was maintained for 24 months. Cerebral microvasculature was increased compared to un-injected control GLUT1+/- mice. AAV-GLUT1 improved the motor function and CSF-glucose levels of GLUT1+/- mice without off-target effects.

Free Research Field

小児神経・遺伝子治療学

Academic Significance and Societal Importance of the Research Achievements

GLUT1DSの治療として、エネルギー代替療法としてケトン食療法があるが、高脂肪食の長期維持に伴う高脂血症および循環器疾患の副作用から長期継続が困難となっていた。今回GLUT1DSモデルマウスに対してAAVベクターを用いた遺伝子治療の有効性を示唆したことは、新規の根治治療として意義があると考える。遺伝子治療により、外因性GLUT1発現が生理的な発現パターンと異なる場合、過発現による神経毒性などの副作用も危惧されるが、本研究では、本来のヒトGLUT1原因遺伝子(SLC2A1)のプロモーター領域を同定して用いるという特色があり、より生理的に近い発現が得られ、より良い治療効果が得られたと考える。