Nakayama Miyu, Moriya Yuu, Ueno Hikaru, Watanabe Takeshi, Hirabayashi Hideki, Yamamoto Syunsuke
Drug Metabolism, Pharmacokinetics and Modeling, Preclinical and Translational Sciences, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
iPSC-Derived Pancreatic Islet Cell (iPIC) Business Unit, Orizuru Therapeutics, Inc, Fujisawa, Kanagawa, Japan.
Mol Ther Methods Clin Dev. 2025 Jul 21;33(3):101538. doi: 10.1016/j.omtm.2025.101538. eCollection 2025 Sep 11.
Induced pluripotent stem cells (iPSCs) have substantial transformative potential in regenerative medicine, enabling tissue repair and restoration. However, their clinical application is limited by tumorigenic risks owing to their pluripotency. Biodistribution studies are crucial for elucidating the fate and tumorigenicity risk of iPSC-derived cell therapy products (CTPs). The lack of standardized biodistribution study protocols has led to inconsistent and unreliable study results, posing difficulties in the drug approval process. Therefore, we conducted a case study on the biodistribution of iPSC-derived pancreatic islet cells to develop a standardized biodistribution assessment protocol for iPSC-derived CTPs. We optimized a droplet digital polymerase chain reaction method targeting human-specific LINE1 sequences and validated its quantitativity for quantification across different tissues using a single calibration curve. We performed a long-term biodistribution study of iPSC-derived pancreatic islet cell in immunodeficient mice to assess biodistribution characteristics, which indicated that they remained localized at the transplantation site for one year, with no migration to other organs, suggesting long-term survival, minimal tumorigenicity risk, and advantages for clinical application. This study provides valuable insights into the standardization of biodistribution protocols for iPSC-derived CTPs.
诱导多能干细胞（iPSC）在再生医学中具有巨大的变革潜力，能够实现组织修复和恢复。然而，由于其多能性，它们的临床应用受到致瘤风险的限制。生物分布研究对于阐明iPSC衍生的细胞治疗产品（CTP）的命运和致瘤风险至关重要。缺乏标准化的生物分布研究方案导致研究结果不一致且不可靠，给药物审批过程带来了困难。因此，我们对iPSC衍生的胰岛细胞的生物分布进行了案例研究，以制定iPSC衍生CTP的标准化生物分布评估方案。我们优化了一种针对人类特异性LINE1序列的液滴数字聚合酶链反应方法，并使用单一校准曲线验证了其在不同组织中定量的定量性。我们对免疫缺陷小鼠体内iPSC衍生的胰岛细胞进行了长期生物分布研究，以评估生物分布特征，结果表明它们在移植部位停留了一年，没有迁移到其他器官，这表明其具有长期存活、最小致瘤风险以及临床应用优势。这项研究为iPSC衍生CTP生物分布方案的标准化提供了有价值的见解。
