Efficient long-term multilineage engraftment of CD33-edited hematopoietic stem/progenitor cells in nonhuman primates.
Efficient long-term multilineage engraftment of CD33-edited hematopoietic stem/progenitor cells in nonhuman primates.
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DOI：
10.1016/j.omtm.2023.101121
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发表时间：
2023-12-14
期刊：
影响因子：
--
通讯作者：
Kiem, Hans-Peter
中科院分区：
文献类型：
--
作者：
Petty, Nicholas E.;Radtke, Stefan;Fields, Emily;Humbert, Olivier;Llewellyn, Mallory J.;Laszlo, George S.;Zhu, Haiying;Jerome, Keith R.;Walter, Roland B.;Kiem, Hans-Peter
目前的免疫治疗靶点通常在肿瘤细胞和正常造血干细胞和祖细胞 (HSPC) 之间共享，从而导致不必要的靶向、脱瘤毒性。因此，删除或修改此类靶标以保护正常 HSPC 引起了极大的兴趣。尽管 HSPC 修饰通常旨在模仿自然发生的表型，但基因编辑细胞的长期持久性和安全性仍需评估。在这里，我们在两只恒河猴的HSPC中删除了CD33的V-set结构域，这是大多数用于治疗CD33阳性恶性肿瘤（包括急性髓系白血病）的抗CD33抗体所靶向的免疫显性结构域，在清髓性预处理后进行了自体移植，并对动物进行了长达3年的跟踪。 CD33 编辑的 HSPC 移植后，中性粒细胞（表达 CD33 的主要细胞类型）的恢复没有任何延迟。没有观察到对血液成分、骨髓干细胞室的重建或骨髓分化潜能的影响。 HSPC 和血细胞谱系中的长期基因编辑高达 20%，并且骨髓谱系上的 CD33 检测严重缺失。总之，HSPC、祖细胞和骨髓谱系上 CD33 V-set 结构域的缺失并未显示出对其归巢和植入潜力或骨髓祖细胞和谱系的分化和功能有任何不利影响。 Petty 及其同事研究了 Cas9 介导的 CD33 消融在非人类灵长类造血过程中的效率和长期持续性。基因修饰的造血干细胞可长期植入，并在所有血统中保持高达 20% 的编辑。这些结果为CD33编辑用于选择和保护的临床应用铺平了道路。
Current immunotherapeutic targets are often shared between neoplastic and normal hematopoietic stem and progenitor cells (HSPCs), leading to unwanted on-target, off-tumor toxicities. Deletion or modification of such targets to protect normal HSPCs is, therefore, of great interest. Although HSPC modifications commonly aim to mimic naturally occurring phenotypes, the long-term persistence and safety of gene-edited cells need to be evaluated. Here, we deleted the V-set domain of CD33, the immune-dominant domain targeted by most anti-CD33 antibodies used to treat CD33-positive malignancies, including acute myeloid leukemia, in the HSPCs of two rhesus macaques, performed autologous transplantation after myeloablative conditioning, and followed the animals for up to 3 years. CD33-edited HSPCs engrafted without any delay in recovery of neutrophils, the primary cell type expressing CD33. No impact on the blood composition, reconstitution of the bone marrow stem cell compartment, or myeloid differentiation potential was observed. Up to 20% long-term gene editing in HSPCs and blood cell lineages was seen with robust loss of CD33 detection on myeloid lineages. In conclusion, deletion of the V-set domain of CD33 on HSPCs, progenitors, and myeloid lineages did not show any adverse effects on their homing and engraftment potential or the differentiation and functionality of myeloid progenitors and lineages. Petty and colleagues investigate the efficiency and long-term persistence of Cas9-mediated ablation of CD33 in non-human primate hematopoiesis. Gene-modified hematopoietic stem cells engrafted long term and maintained up to 20% editing across all blood lineages. These results pave the way for the clinical application of CD33 editing for selection and protection.
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发表时间：
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通讯作者：
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