Research progress and existing problems in the industrialization of stem cell drugs
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摘要:
干细胞是一类具有多向分化潜能和自我更新能力的原始未分化细胞，有再生人体各种组织和器官的潜在功能。干细胞药物开发是生命科学的前沿研究领域。干细胞在不同重大疑难性疾病的治疗上开展了广泛的临床试验，在某些适应证上作为药物获得批准上市，有着广阔的产业化前景。本综述通过介绍干细胞药物在全球及国内产业化方面的进展，及产业化存在的主要问题，如干细胞药物的有效性、质量控制、安全性等，为干细胞药物的开发提供参考和思路，以加快干细胞药物的产业化进程。
Abstract:Stem cells, which are a type of primitive cells with multipotent differentiation potential and self-renewal ability, have the potential to regenerate various tissues and organs. Stem cell drug development is a frontier research field in life sciences. Extensive clinical trials involving stem cells have been conducted for different complicated diseases. Some stem cells have been approved as drugs for some indications, indicating their broad industrial prospects. This review introduces the progress of stem cell drugs around the world, especially in China, and discusses the main problems in the industrialization of stem cell drugs, such as their effectiveness, quality control and safety, so as to provide some reference and insight for the development and rapid industrialization of stem cell drugs.
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Keywords:
- stem cell /
- industrialization /
- effectiveness /
- quality control
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表 1 全球已上市干细胞产品
序号 获批国家/地区 获批时间 商品名 公 司 细胞来源 适应证 1 澳大利亚 2010 MPC Mesoblast 自体间质前体细胞产品 骨修复 2 韩国 2010 Queencell Anterogen 脂肪来源间充质干细胞 皮下组织缺损 3 韩国 2011 Cellgram Pharmicell 骨髓来源间充质干细胞 急性心肌梗死 4 加拿大 2012 Prochymal Osiris Therapeutics/Mesoblast 人异体骨髓来源间充质干细胞 移植物抗宿主病 5 韩国 2012 Cupistem Anterogen 脂肪来源间充质干细胞 克罗恩病并发肛瘘 6 韩国 2012 Cartistem Medipost 脐带血间充质干细胞 退行性关节炎 7 美国 2012 MultiStem Athersys 骨髓等来源的多能成体祖细胞 赫尔勒综合征 8 韩国 2014 Neuronata-R Corestem 骨髓来源间充质干细胞 肌萎缩侧索硬化 9 欧盟 2015 Holoclar Chiesi Farmaceutici 人类自体角膜干细胞 中重度角膜缘干细胞缺乏症 10 印度 2016 Stempeucel Stempeutics Research PVT 骨髓来源间充质干细胞 严重肢体缺血 11 日本 2016 Temcell JCR Pharmaceuticals 异体骨髓来源间充质干细胞 移植物抗宿主病 12 欧盟
日本2018
2021Alofisel TiGenix/Takeda 异体脂肪间充质干细胞 复杂性克罗恩病并发肛瘘 13 日本 2018 Stemirac Nipro 骨髓来源间充质干细胞 脊髓损伤 
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表 2 干细胞药物产业化存在的问题及解决方案
存在问题类别 存在问题内容 解决方案 干细胞药物的有效性 缺少生物有效性指标 进行转录组学、蛋白组学研究，筛选针对适应证的生物有效性指标 干细胞功能不强 通过基因修饰增加功能 临床适应证和入组标准不合适 对适应证进行细分；严格合理制定入组标准 干细胞药物的质量可控 干细胞的异质性 制定供者及组织筛选标准；确定合理的关键工艺参数（CPP）范围
建立PAT在线、动态分析过程干细胞的关键质量属性（CQA）
认识不足针对适应证开展机制和质量研究，充分了解和确认关键质量属性，
尤其是生物效力的质量属性干细胞药物的安全性 缺乏可靠的微生物检测快速放行方法 开发新的快速放行方法并进行药典方法的替代验证 生物安全性控制不足 优化工艺减少残留未分化细胞及非细胞致瘤性因素
开发灵敏度高的未分化细胞的检测方法
监测细胞分化过程中的基因突变
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