Establishment of iPS cell-based strategy for elucidating the pathogenesis of autoimmune diseases and discovery of therapeutic targets

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08800
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: The University of Tokyo
• Principal Investigator: Shoda Hirofumi 東京大学, 医学部附属病院, 准教授 (20529036)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 全身性エリテマトーデス / iPS細胞 / インターフェロン

Outline of Final Research Achievements

The aim of this study is to elucidate the pathogenesis of autoimmune diseases and to establish basic technologies and strategies for drug discovery by applying iPS cells. Using iPS cells established from systemic lupus erythematosus (SLE) patients, we performed functional analysis of newly identified rare variants of OASL gene. In particular, we created wild type and mutated iPS cell strains by genome editing. OASL variants were found to enhance the type I interferon (IFN) response to dsRNA stimulation in dendritic cells, suggesting a contribution to SLE pathogenesis. This study is expected to establish a technical fundation for studying the involvement of rare variants in autoimmune diseases and lead to future drug discovery research.

Free Research Field

臨床免疫学

Academic Significance and Societal Importance of the Research Achievements

iPS細胞を活用した自己免疫疾患研究および創薬研究の技術的基盤の開発が本研究の最も重要な意義である。SLEに関連するOASL遺伝子変異の新規同定は、SLE病態の解明および新規創薬標的として、臨床応用につながる可能性がある。またOASL遺伝子変異はSLE患者においてOdds ratio 8と高頻度で認められたが、これは従来のSNPにおけるリスクよりかなり高い寄与が関与される。この結果は、特定の患者における自己免疫疾患の遺伝的メカニズムにおいてrare variantはより強く関与している可能性を示唆し、自己免疫性疾患を遺伝学的に理解するうえで重要な知見の可能性がある。