In this study, we take an important step toward clinical translation by generating the first canine‐induced neural stem cells (iNSCs). We explore key aspects of scale‐up, persistence, and safety of personalized iNSC therapy in autologous canine surgery models. iNSCs are a promising new approach to treat aggressive cancers of the brain, including the deadly glioblastoma. Created by direct transdifferentiation of fibroblasts, iNSCs are known to migrate through the brain, track down invasive cancer foci, and deliver anticancer payloads that significantly reduce tumor burden and extend survival of tumor‐bearing mice. Here, skin biopsies were collected from canines and converted into the first personalized canine iNSCs engineered to carry TNFα‐related apoptosis‐inducing ligand (TRAIL) and thymidine kinase (TK), as well as magnetic resonance imaging (MRI) contrast agents for in vivo tracking. Time‐lapse analysis showed canine iNSCs efficiently migrate to human tumor cells, and cell viability assays showed both TRAIL and TK monotherapy markedly reduced tumor growth. Using intraoperative navigation and two delivery methods to closely mimic human therapy, canines received autologous iNSCs either within postsurgical cavities in a biocompatible matrix or via a catheter placed in the lateral ventricle. Both strategies were well tolerated, and serial MRI showed hypointense regions at the implant sites that remained stable through 86 days postimplant. Serial fluid sample testing following iNSC delivery showed the bimodal personalized therapy was well tolerated, with no iNSC‐induced abnormal tissue pathology. Overall, this study lays an important foundation as this promising personalized cell therapy advances toward human patient testing.

中文翻译：

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个性化诱导神经干细胞治疗：大型动物模型中的生成、移植和安全性

在这项研究中，我们通过产生第一个犬诱导神经干细胞（iNSC），向临床转化迈出了重要一步。我们探讨了自体犬手术模型中个性化 iNSC 治疗的扩大规模、持久性和安全性的关键方面。iNSC 是治疗侵袭性脑癌（包括致命的胶质母细胞瘤）的一种有前景的新方法。iNSC 由成纤维细胞直接转分化产生，可在大脑中迁移，追踪侵袭性癌灶，并提供抗癌有效负载，显着减轻肿瘤负荷并延长荷瘤小鼠的生存期。在这里，从犬科动物身上收集了皮肤活检样本，并将其转化为第一个个性化的犬类 iNSC，该 iNSC 被设计为携带 TNFα 相关凋亡诱导配体 (TRAIL) 和胸苷激酶 (TK)，以及用于体内的磁共振成像 (MRI) 造影剂追踪。延时分析显示犬 iNSC 有效迁移至人类肿瘤细胞，细胞活力测定显示 TRAIL 和 TK 单一疗法均显着减少肿瘤生长。使用术中导航和两种输送方法来密切模仿人类治疗，犬科动物在生物相容性基质的术后腔内或通过放置在侧脑室的导管接受自体 iNSC。两种策略均具有良好的耐受性，连续 MRI 显示植入部位的低信号区域在植入后 86 天保持稳定。iNSC 递送后的连续液体样本测试显示双模式个性化治疗耐受性良好，没有 iNSC 诱导的异常组织病理学。总的来说，这项研究为这种有前途的个性化细胞疗法向人类患者测试的进展奠定了重要的基础。