干细胞产品正逐渐进入用于治疗视网膜退化症的早期临床试验阶段。该领域通过经验教训逐渐了解了用于临床前和临床使用的细胞的可比性。如果没有这方面的认识，支持将临床前数据转化为临床研究的数据可能无法充分反映随后在患者中使用的临床级细胞的性能。在Royal College of Surgeons (RCS) 大鼠（一种视网膜色素变性的啮齿动物模型）的亚视网膜空间内注射了研究级人类神经前体细胞 (hNPC) 和临床级hNPC（称为CNS10-NPC）。对CNS10-NPC进行了在同一大鼠模型中进行了新药研究授权调查 (IND)。最后，通过使用眼球大小与人类相当的Yucatan 迷你猪作为大型动物模型，对眼外视网膜细胞输送的手术方法进行了优化。 无论是研究级hNPC还是临床级hNPC，都能以剂量依赖的方式存活并提供功能和形态保护，优化的细胞剂量在IND研究中得到定义和使用。移植的CNS10-NPC从注射部位迁移出来，而不会分化为视网膜细胞表型。此外，CNS10-NPC在符合良好实验实践 (GLP) 的毒性和致瘤性研究中表现出长期存活、安全性和有效性，即使在最大可输送剂量下也未观察到细胞过度生长。最后，通过使用与人类眼球大小相当的Yucatan 迷你猪作为大型动物模型，我们对临床中眼外视网膜细胞输送的手术方法进行了优化。 这些广泛的研究支持了经批准的IND以及CNS10-NPC用于进行中的视网膜色素变性的1/2a期临床试验 (NCT04284293) 的转化。© 2023. BioMed Central Ltd., part of Springer Nature.

Stem cell products are increasingly entering early stage clinical trials for treating retinal degeneration. The field is learning from experience about comparability of cells proposed for preclinical and clinical use. Without this, preclinical data supporting translation to a clinical study might not adequately reflect the performance of subsequent clinical-grade cells in patients.Research-grade human neural progenitor cells (hNPC) and clinical-grade hNPC (termed CNS10-NPC) were injected into the subretinal space of the Royal College of Surgeons (RCS) rat, a rodent model of retinal degeneration such as retinitis pigmentosa. An investigational new drug (IND)-enabling study with CNS10-NPC was performed in the same rodent model. Finally, surgical methodology for subretinal cell delivery in the clinic was optimized in a large animal model with Yucatan minipigs.Both research-grade hNPC and clinical-grade hNPC can survive and provide functional and morphological protection in a dose-dependent fashion in RCS rats and the optimal cell dose was defined and used in IND-enabling studies. Grafted CNS10-NPC migrated from the injection site without differentiation into retinal cell phenotypes. Additionally, CNS10-NPC showed long-term survival, safety and efficacy in a good laboratory practice (GLP) toxicity and tumorigenicity study, with no observed cell overgrowth even at the maximum deliverable dose. Finally, using a large animal model with the Yucatan minipig, which has an eye size comparable to the human, we optimized the surgical methodology for subretinal cell delivery in the clinic.These extensive studies supported an approved IND and the translation of CNS10-NPC to an ongoing Phase 1/2a clinical trial (NCT04284293) for the treatment of retinitis pigmentosa.© 2023. BioMed Central Ltd., part of Springer Nature.