Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
J Transl Med. 2023 Sep 25;21(1):650. doi: 10.1186/s12967-023-04501-z.
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.
干细胞产品越来越多地进入治疗视网膜变性的早期临床试验。该领域正在从经验中学习，了解用于临床前和临床用途的细胞的可比性。如果没有这种可比性，支持转化为临床研究的临床前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。
研究级人神经祖细胞（hNPC）和临床级 hNPC（称为 CNS10-NPC）被注射到 Royal College of Surgeons（RCS）大鼠的视网膜下空间，这是一种类似于色素性视网膜炎的视网膜变性的啮齿动物模型。在同一啮齿动物模型中进行了 CNS10-NPC 的新药临床试验（IND）启用研究。最后，在具有尤卡坦小型猪的大动物模型中优化了用于临床的视网膜下细胞递送的手术方法。
研究级 hNPC 和临床级 hNPC 均可在 RCS 大鼠中以剂量依赖性方式存活并提供功能和形态保护，并且定义了最佳细胞剂量并用于 IND 启用研究。移植的 CNS10-NPC 从注射部位迁移，没有分化为视网膜细胞表型。此外，CNS10-NPC 在良好实验室规范（GLP）毒性和致瘤性研究中表现出长期存活、安全性和疗效，即使在最大可输送剂量下也没有观察到细胞过度生长。最后，使用具有与人眼大小相当的尤卡坦小型猪的大动物模型，我们优化了用于临床的视网膜下细胞递送的手术方法。
这些广泛的研究支持了批准的 IND，并将 CNS10-NPC 转化为正在进行的 1/2a 期临床试验（NCT04284293），用于治疗色素性视网膜炎。
