mRNA therapy for the treatment of autoimmune diseases that produces chimeric antigen receptor regulatory T cells in vivo

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K19541
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Cabral Horacio 東京大学, 大学院工学系研究科(工学部), 准教授 (10533911)
• Co-Investigator(Kenkyū-buntansha): 持田 祐希 公益財団法人川崎市産業振興財団(ナノ医療イノベーションセンター), ナノ医療イノベーションセンター, 副主幹研究員 (60739134) ; 松元 亮 東京医科歯科大学, 生体材料工学研究所, 教授 (70436541) ; 宮崎 拓也 地方独立行政法人神奈川県立産業技術総合研究所, 貼るだけ人工膵臓グループ (松元G), 非常勤研究員 (80844779)
• Project Period (FY): 2022-06-30 – 2024-03-31
• Keywords: mRNA / polymeric micelles / in situ Treg / Immunosuppression

Outline of Final Research Achievements

Herein, we used polymeric micelles installed with anti-CD3 F(ab')2 antibodies to effectively deliver mRNA to T cells, aiming to induce the production of regulatory T cells (Tregs). The mRNA was derived from in vitro transcription of a plasmid encoding Foxp3 protein. Foxp3 can facilitate the generation of Tregs, known for their immune regulatory role. The micelles loaded the mRNA by self-assembly in aqueous conditions. Moreover, the surface of the micelles was modified with anti-CD3 F(ab')2 by click chemistry. The resulting micelles were around 100 nm in diamter. These micelles selectively targeted CD3+ T cells, both in vitro and in vivo, resulting in the production of Tregs. Remarkably, the modified T cells displayed an anti-inflammatory profile, characterized by the secretion of cytokines such as IL-10, IL-4, and Tgf-beta. These findings support the potential of this approach for generating immunomodulating T cells in various disease contexts.

Free Research Field

Drug and gene delivery

Academic Significance and Societal Importance of the Research Achievements

By using micelles to deliver mRNA encoding Foxp3 protein, we can induce Tregs that mediate immunosuppression, which has potential for treating autoimmune diseases, allergies and inflammatory disorders. The approach could reduce costs and burden of cellular therapies by in situ generation of Tregs.