Retinal regenerative therapies hold great promise for the treatment of inherited retinal degenerations (IRDs). Studies in preclinical lower mammal models of IRDs have suggested visual improvement following retinal photoreceptor precursors transplantation, but there is limited evidence on the ability of these transplants to rescue retinal damage in higher mammals. The purpose of this study was to evaluate the therapeutic potential of photoreceptor precursors derived from clinically compliant induced pluripotent stem cells (iPSCs). Photoreceptor precursors were sub-retinally transplanted into non-human primates (Macaca fascicularis). The cells were transplanted both in naïve and cobalt chloride-induced retinal degeneration models who had been receiving systemic immunosuppression for one week prior to the procedure. Optical coherence tomography, fundus autofluorescence imaging, electroretinography, ex vivo histology and immunofluorescence staining were used to evaluate retinal structure, function and survival of transplanted cells. There were no adverse effects of iPSC-derived photoreceptor precursors on retinal structure or function in naïve NHP models, indicating good biocompatibility. In addition, photoreceptor precursors injected into cobalt chloride-induced retinal degeneration NHP models demonstrated an ability both to survive and to mature into cone photoreceptors at 3 months post-transplant. Optical coherence tomography showed restoration of retinal ellipsoid zone post-transplantation. These findings demonstrate the safety and therapeutic potential of clinically compliant iPSC-derived photoreceptor precursors as a cell replacement source for future clinical trials.

中文翻译：

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cGMP 级人 iPSC 衍生的视网膜光感受器前体细胞可挽救非人灵长类动物的视锥光感受器损伤

视网膜再生疗法在治疗遗传性视网膜变性 (IRD) 方面具有广阔前景。对 IRD 的临床前低等哺乳动物模型的研究表明，视网膜光感受器前体移植后视力有所改善，但关于这些移植物在高等哺乳动物中挽救视网膜损伤的能力的证据有限。本研究的目的是评估来自临床顺应性诱导多能干细胞 (iPSC) 的光感受器前体的治疗潜力。光感受器前体被亚视网膜移植到非人类灵长类动物 (Macaca fascicularis) 中。这些细胞被移植到幼稚和氯化钴诱导的视网膜变性模型中，这些模型在手术前已经接受了一周的全身免疫抑制。光学相干断层扫描，眼底自发荧光成像、视网膜电图、离体组织学和免疫荧光染色用于评估移植细胞的视网膜结构、功能和存活。在幼稚的 NHP 模型中，iPSC 衍生的光感受器前体对视网膜结构或功能没有不利影响，表明具有良好的生物相容性。此外，注射到氯化钴诱导的视网膜变性 NHP 模型中的光感受器前体显示出在移植后 3 个月存活并成熟为视锥光感受器的能力。光学相干断层扫描显示移植后视网膜椭球区的恢复。这些发现证明了符合临床要求的 iPSC 衍生的光感受器前体作为未来临床试验的细胞替代来源的安全性和治疗潜力。