Long-Term Safety and Function of RPE from Human Embryonic Stem Cells in Preclinical Models of Macular Degeneration
Long-Term Safety and Function of RPE from Human Embryonic Stem Cells in Preclinical Models of Macular Degeneration
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DOI：
10.1002/stem.149
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发表时间：
2009-01-01
期刊：
影响因子：
5.2
通讯作者：
Lund, Raymond
中科院分区：
文献类型：
--
作者：
Lu, Bin;Malcuit, Christopher;Lund, Raymond
在人类ESC（hESC）疗法进入临床之前，安全性和有效性评估至关重要。两个重要的早期潜在hESC应用是使用视网膜色素上皮（RPE）治疗年龄相关性黄斑变性和Stargardt病，这是一种无法治疗的导致早发性失明的黄斑营养不良形式。在这里，我们显示了在RCS大鼠和Elov 14小鼠中使用hESC衍生的RPE的长期功能拯救，RCS大鼠和Elov 14小鼠分别是视网膜变性和Stargardt的动物模型。符合良好生产规范的hESC-RPE在RCS大鼠中的视网膜下移植物中存活延长的时间段（>220天）。这些细胞以剂量依赖的方式维持视觉功能和感光器的完整性，而没有畸胎瘤形成或不良病理反应。在RCS大鼠存活>60天时记录接近正常的功能测量。为了进一步解决安全性问题，在NIH III免疫缺陷小鼠模型中进行了符合药物非临床研究质量管理规范的研究。长期数据（跨越动物的寿命）显示在视网膜下hESC-RPE移植后没有畸胎瘤/肿瘤形成的肉眼或显微镜证据。这些结果表明，人胚胎干细胞可以作为一个潜在的安全和取之不尽的RPE的来源，有效地治疗一系列视网膜退行性疾病。干细胞2009; 27：2126-2135
Assessments of safety and efficacy are crucial before human ESC (hESC) therapies can move into the clinic. Two important early potential hESC applications are the use of retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration and Stargardt disease, an untreatable form of macular dystrophy that leads to early-onset blindness. Here we show long-term functional rescue using hESC-derived RPE in both the RCS rat and Elov14 mouse, which are animal models of retinal degeneration and Stargardt, respectively. Good Manufacturing Practice-compliant hESC-RPE survived subretinal transplantation in RCS rats for prolonged periods (>220 days). The cells sustained visual function and photo-receptor integrity in a dose-dependent fashion without teratoma formation or untoward pathological reactions. Near-normal functional measurements were recorded at >60 days survival in RCS rats. To further address safety concerns, a Good Laboratory Practice-compliant study was carried out in the NIH III immune-deficient mouse model. Long-term data (spanning the life of the animals) showed no gross or microscopic evidence of teratoma/tumor formation after subretinal hESC-RPE transplantation. These results suggest that hESCs could serve as a potentially safe and inexhaustible source of RPE for the efficacious treatment of a range of retinal degenerative diseases. STEM CELLS 2009; 27: 2126-2135