Pathogenesis of Gaucher disease neurological dysfunction on the basis of the construction of a model of the human blood-brain barrier

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15297
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Tokyo University of Pharmacy and Life Science (2022-2023); Kumamoto University (2021)
• Principal Investigator: Shirai Remina 東京薬科大学, 生命科学部, 嘱託助教 (40870754)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: ゴーシェ病 / iPS細胞 / 血液脳関門 / CRISPR

Outline of Final Research Achievements

In Gaucher's disease, glucocerebroside accumulates in tissues throughout the body and causes central nervous system damage. Existing enzyme replacement drugs have difficulty in passing through the blood-brain barrier and are unlikely to be effective against the neurological symptoms. In this study, a blood-brain barrier model was constructed from human cells to elucidate the dysfunction of Gaucher disease.
First, vascular endothelial cells, neurons and microglia were induced from healthy subjects and Gaucher disease-derived iPS cells. When neural stem cells and microglia were co-cultured and their viability was examined, the number of surviving neural stem cells derived from Gaucher's disease was significantly reduced. Gaucher disease-like pericytes were also established by transfection of primary cultured human pericytes with CRISPR mRNA, and there was no difference in the expression of pericyte markers.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

これまでに動物細胞を用いた血液脳関門モデルが開発されたが、血液脳関門トランスポータータンパク質発現量がヒトと動物で異なる、という難点がある。本研究はこれらの問題点を克服すべく、全ての血液脳関門モデル細胞をヒト細胞から樹立すべく立案された。またゴーシェ病様神経細胞、ミクログリア、ペリサイトを用いてゴーシェ病の障害機能解明を行った。
本研究によりゴーシェ病の根治療法の開発が進展することは非常に意義が高く、これまで血液脳関門の存在により治療が困難だった神経疾患の治療法開発という点でも社会劇意義は特に大きい。