Gupta Rohan, Bunea Irina, Alvisio Bruno, Barone Francesca, Gupta Rishabh, Baker Dara, Qian Haohua, Daniele Elena, Contreary Casey G, Montford Jair, Sharma Ruchi, Maminishkis Arvydas, Singh Mandeep S, Magone De Quadros Costa Maria Teresa, Kashani Amir H, Amaral Juan, Bharti Kapil
Ocular and Stem Cell Translational Research Section, National Eye Institute, NIH, Bethesda, Maryland, USA.
BioTeam, Life Sciences IT Consulting, Middleton, Massachusetts, USA.
JCI Insight. 2025 May 22;10(10). doi: 10.1172/jci.insight.179246.
Dry age-related macular degeneration (AMD) is a leading cause of untreatable vision loss. In advanced cases, retinal pigment epithelium (RPE) cell loss occurs alongside photoreceptor and choriocapillaris degeneration. We hypothesized that an RPE-patch would mitigate photoreceptor and choriocapillaris degeneration to restore vision. An induced pluripotent stem cell-derived RPE (iRPE) patch was developed using a clinically compatible manufacturing process by maturing iRPE cells on a biodegradable poly(lactic-co-glycolic acid) (PLGA) scaffold. To compare outcomes, we developed a surgical procedure for immediate sequential delivery of PLGA-iRPE and/or PLGA-only patches in the subretinal space of a pig model of laser-induced outer retinal degeneration. Deep learning algorithm-based optical coherence tomography (OCT) image segmentation verified preservation of the photoreceptors over the areas of PLGA-iRPE-transplanted retina and not in laser-injured or PLGA-only-transplanted retina. Adaptive optics imaging of individual cone photoreceptors further supported this finding. OCT-angiography revealed choriocapillaris regeneration in PLGA-iRPE- and not in PLGA-only-transplanted retinas. Our data, obtained using clinically relevant techniques, verified that PLGA-iRPE supports photoreceptor survival and regenerates choriocapillaris in a laser-injured pig retina. Sequential delivery of two 8 mm2 transplants allows for testing of surgical feasibility and safety of the double dose. This work allows one surgery to treat larger and noncontiguous retinal degeneration areas.
干性年龄相关性黄斑变性（AMD）是导致不可治疗性视力丧失的主要原因。在晚期病例中，视网膜色素上皮（RPE）细胞丢失与光感受器和脉络膜毛细血管变性同时发生。我们假设RPE贴片可以减轻光感受器和脉络膜毛细血管变性以恢复视力。通过在可生物降解的聚乳酸-乙醇酸共聚物（PLGA）支架上使诱导多能干细胞衍生的RPE（iRPE）细胞成熟，利用临床兼容的制造工艺开发了一种iRPE贴片。为了比较结果，我们开发了一种手术程序，用于在激光诱导的视网膜外层变性猪模型的视网膜下间隙中立即顺序递送PLGA-iRPE和/或仅PLGA贴片。基于深度学习算法的光学相干断层扫描（OCT）图像分割证实，在PLGA-iRPE移植视网膜区域的光感受器得以保留，而在激光损伤或仅PLGA移植的视网膜中则没有。对单个视锥光感受器的自适应光学成像进一步支持了这一发现。OCT血管造影显示PLGA-iRPE移植的视网膜中有脉络膜毛细血管再生，而仅PLGA移植的视网膜中没有。我们使用临床相关技术获得的数据证实，PLGA-iRPE可支持激光损伤猪视网膜中的光感受器存活并使脉络膜毛细血管再生。顺序递送两个8平方毫米的移植物可以测试双倍剂量的手术可行性和安全性。这项工作使得一次手术能够治疗更大且不连续的视网膜变性区域。
