Generation and testing of clinical-grade exosomes for pancreatic cancer
Generation and testing of clinical-grade exosomes for pancreatic cancer
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DOI：
10.1172/jci.insight.99263
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发表时间：
2018-04-19
期刊：
影响因子：
8
通讯作者：
Kalluri, Raghu
中科院分区：
文献类型：
--
作者：
Mendt, Mayela;Kamerkar, Sushrut;Kalluri, Raghu
外泌体是由所有细胞产生的细胞外囊泡，其具有将遗传物质（包括外源加载的siRNA）有效转移至癌细胞的显著能力。在这里，我们报告了采用良好生产规范（GMP）标准的基于生物反应器的临床级外泌体的大规模生产。建立了标准操作程序以产生具有靶向致癌Kras的能力的工程化外泌体（iExosomes）。在多项体外和体内研究中测试了临床级GMP iExosomes，以证实对致癌Kras的抑制和几种胰腺癌小鼠模型存活率的增加。我们进行研究以确定与化疗组合的保质期、生物分布、毒理学特征和功效，以告知GMP iExosomes的未来临床测试。总的来说，这份报告说明了为人类疾病的各种疗法产生临床级外泌体的过程和可行性。
Exosomes are extracellular vesicles produced by all cells with a remarkable ability to efficiently transfer genetic material, including exogenously loaded siRNA, to cancer cells. Here, we report on a bioreactor-based, large-scale production of clinical-grade exosomes employing good manufacturing practice (GMP) standards. A standard operating procedure was established to generate engineered exosomes with the ability to target oncogenic Kras (iExosomes). The clinical-grade GMP iExosomes were tested in multiple in vitro and in vivo studies to confirm suppression of oncogenic Kras and an increase in the survival of several mouse models with pancreatic cancer. We perform studies to determine the shelf life, biodistribution, toxicology profile, and efficacy in combination with chemotherapy to inform future clinical testing of GMP iExosomes. Collectively, this report illustrates the process and feasibility of generating clinical-grade exosomes for various therapies of human diseases.