Lu Bin, Malcuit Christopher, Wang Shaomei, Girman Sergej, Francis Peter, Lemieux Linda, Lanza Robert, Lund Raymond
Casey Eye Institute, Oregon Health and Science University, Portland, Oregon 97239, USA.
Stem Cells. 2009 Sep;27(9):2126-35. doi: 10.1002/stem.149.
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 photoreceptor 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.
在人类胚胎干细胞（hESC）疗法能够进入临床之前，对其安全性和有效性的评估至关重要。hESC早期两个重要的潜在应用是利用视网膜色素上皮（RPE）治疗年龄相关性黄斑变性和Stargardt病，后者是一种无法治愈的黄斑营养不良形式，可导致早发性失明。在这里，我们展示了在RCS大鼠和Elov14小鼠中使用hESC来源的RPE进行长期功能挽救，这两种动物分别是视网膜变性和Stargardt病的动物模型。符合药品生产质量管理规范（GMP）的hESC-RPE在RCS大鼠的视网膜下移植中存活了较长时间（>220天）。这些细胞以剂量依赖的方式维持视觉功能和光感受器完整性，没有形成畸胎瘤或出现不良病理反应。在RCS大鼠存活>60天时记录到接近正常的功能测量结果。为了进一步解决安全性问题，在国立卫生研究院（NIH）III型免疫缺陷小鼠模型中开展了一项符合良好实验室规范（GLP）的研究。长期数据（涵盖动物的整个生命周期）显示，视网膜下hESC-RPE移植后没有明显或微观的畸胎瘤/肿瘤形成证据。这些结果表明，hESC可能是一种潜在安全且取之不尽的RPE来源，可有效治疗一系列视网膜退行性疾病。
