Tumor-tropic liposome-mediated therapeutic delivery of mRNA for the treatment of adolescent and young adult cancers.

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08227
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Shinshu University
• Principal Investigator: Saito Shoji 信州大学, 学術研究院医学系(医学部附属病院), 講師 (10623762)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: リポソーム / ｍRNA医薬 / Caspase 9 / アポトーシス / 遺伝子治療

Outline of Final Research Achievements

Cancer gene therapy can be potential therapeutics for advanced/refractory cancers. Combining tumor-tropic lipid nanoparticles (LNPs) and inducible caspase-9 (iC9) mRNA, we aimed to develop a novel treatment strategy for refractory breast cancer. LNP’s anti-tumor effects were tested in vitro in three breast cancer cell lines: MDA-MB231, SKBR3, and MCF-7. LNPs could efficiently deliver encapsulated GFP mRNA to all three cancer cell lines. Furthermore, LNPs encapsulated with iC9 mRNA (iC9-LNPs) and CID showed cytotoxic activity against all cancer cell lines in vitro. Interestingly, susceptibility to iC9 gene therapy was heterogeneous among cancer cell lines. Quantification of apoptosis-related genes suggested that a high BAX/Bcl-2 ratio might be associated with iC9-LNP+CID susceptibility. Thus, cancer gene therapy using iC9-LNPs and CID could be a promising alternative for the treatment of breast cancers, especially for aggressive breast cancers.

Free Research Field

血液腫瘍、免疫療法、遺伝子治療

Academic Significance and Societal Importance of the Research Achievements

本研究において、難治性乳がんに対する、腫瘍指向性脂質ナノ粒子(LNP)と誘導性カスパーゼ9(iC9)mRNAを組み合わせた新規遺伝子治療法の開発に成功した。本研究では乳がんを対象に治療効果を検証したが、本遺伝子治療法は、理論的にはがん種によらず有効性が示せるため、さまざまながん種に対する治療法に応用できる。また、アポトーシス関連の解析を行ったところ、乳がんにおいてはより悪性度の高いがん種において感受性が高いことを示した。このため、本疾患は難治性がんに対する有望な治療法として応用できる可能性がある。