然而，由 CRISPR-Cas9/AAV6 介导的细胞反应会损害经过 HDR 编辑的 HSPC 的长期再增殖潜能，对临床转化的安全性和有效性产生不利影响。 撰文丨王聪 编辑丨王多鱼 排版丨水成文 利用 同源定向修复 （HDR） 技术对造血干细胞/祖细胞 （HSPC） 进行基因编，为遗传性疾病的长期基因校正带来了希望。 2025 年 6 月 3 日，意大利 圣拉斐尔科学研究所 （IRCCS） 的研究人员在 Cell 子刊 Cell Reports Medicine 上发表了题为 ： Senescence and inflammation are unintended adverse consequences of CRISPR-Cas9/AAV6-mediated gene editing in hematopoietic stem cells 的研究论文。 该研究表明， CRISPR-Cas9/AAV6 介导的对 造血干细胞 的基因编辑，会带来 衰老 和 炎症 等意外不良后果，从而影响基因治疗效果和安全性。该研究进一步 发现 ，使用 IL-1 信号拮抗剂 阿那白滞素 （Anakinra） 治疗， 可以增强 H ...

Core Viewpoint - Acute Myeloid Leukemia (AML) presents significant treatment challenges due to the inherent heterogeneity of leukemic cells and the resistance of leukemia stem cells (LSC) to chemotherapy, leading to poor prognosis and high relapse rates [2][3]. Group 1: AML Characteristics and Challenges - AML is characterized by the obstruction of differentiation and abnormal proliferation of immature myeloid cells, resulting in hematopoietic dysfunction and life-threatening cytopenias [2]. - The incidence of AML increases with age, with over two-thirds of diagnoses occurring in individuals over 55 years old. The overall survival rate is approximately 40%-45% for patients under 65, while it drops to 10%-15% for those over 65 [2]. - More than half of AML patients experience disease relapse within one year, and less than one-third achieve durable remission [2]. Group 2: CAR-T Cell Therapy and CD97 Targeting - CAR-T cell therapy has shown success in treating refractory or relapsed B-cell malignancies but has not met expectations in AML due to the lack of specific targets like CD19 found in B-cells [3]. - Most antigens expressed on AML cells and LSCs are also present on normal cells, particularly hematopoietic stem cells (HSC), leading to off-target toxicity and complications such as neutropenia, anemia, and thrombocytopenia [3]. - A study published on May 26, 2025, identified CD97 as an ideal target for CAR-T cell therapy in AML, demonstrating that CD97-directed CAR-T cells could effectively eradicate AML in various xenograft models [3][9]. Group 3: CD97 Characteristics and Implications - CD97, encoded by the ADGRE5 gene, is a member of the adhesion G protein-coupled receptor family and is associated with promoting the invasion of various cancer cells, including those in AML [5]. - CD97 expression is significantly elevated in primary AML cells and LSCs compared to normal bone marrow cells, and its high expression correlates with poor prognosis in AML patients [5]. - CD97 plays a critical role in the proliferation and survival of AML cells, maintaining their undifferentiated state, making it a promising therapeutic target [5]. Group 4: Research Findings on CD97-targeted CAR-T Cells - The research team utilized CRISPR-Cas9 technology to knock out CD97 in T cells, creating CD97 KO CAR-T cells that effectively eliminate AML cells while showing tolerable toxicity to HSCs [6][9]. - Optimized CD97 KO CAR-T cells demonstrated sustained anti-tumor activity in vitro and in various xenograft mouse models, indicating their potential for durable therapeutic effects [6][9]. - The study supports CD97 as a promising target for CAR-T cell therapy in AML, highlighting the importance of gene editing strategies to mitigate self-targeting issues in T cells [9].