mRNA-LNP-delivered synthetic transcription activator cancer therapy published / Epstein-Barr病毒阳性上皮癌的基因转录激活剂的纳米溶癌疗法

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mRNA-LNP-delivered synthetic transcription activator cancer therapy published / Epstein-Barr病毒阳性上皮癌的基因转录激活剂的纳米溶癌疗法

June 24, 2024 | | Press releases, Publications |

While gene editing is currently the major approach used in CRISPR-based therapeutics, epigenetic editing – changing histone modifications, DNA methylation, or gene expression levels without changing genetic sequences – could be a powerful alternative in some diseases.

We collaborated with scientists from Chinese University of Hong Kong, Karolinska Institutet, Jackson Laboratory and Arizona State University, to develop an RNA-lipid nanoparticle (LNP)-delivered epigenetic editing approach for cancer therapy in Epstein-Barr virus (EBV)-associated malignancies.

EBV infection is prevalent across the global population. Latent EBV infection may lead to a variety of malignancies, including nasopharyngeal carcinoma, some forms of gastric cancers and lymphoma, etc. Continued presence of viral genome in latent state in EBV-associated cancer cells represent a unique target for therapeutic interventions. A potential approach to eliminate EBV-associated cancer cells is by activating EBV lytic cycle from latent state to induce growth arrest, apoptosis and cell rupture.

We used CRISPR- and TALE-based activators to turn on lytic genes on EBV genomes within cancer cells. For delivery, we used lipid nanoparticle to encapsulate nucleoside-modified mRNA encoding these synthetic activators and showed potency and safety of these LNPs-delivered activator in suppressing tumor growth in mouse models in vivo. These results demonstrate the potential of epigenetic editing approach for cancer therapeutics.

[Jump to the paper, press releases and media report]

Epstein-Barr病毒 (EBV)感染在全球人群中很普遍。潜在的EBV感染可能导致各种恶性肿瘤，包括鼻咽癌、胃癌和淋巴癌等。在EBV相关的癌症细胞中持续存在且处于潜伏状态的病毒基因组为癌症的治疗和干预提供了一个独特的靶点。研究团队通过激活潜伏状态的EBV裂解周期来诱导细胞生长停滞、凋亡和破裂直至消除，从而达到歼灭癌细胞的目的。

2024年5月3日，中国科学院动物研究所郑瑚团队联合香港中文大学及美国杰克逊实验室研究团队在Nature Communications期刊发表了题为“Synthetic BZLF1-targeted transcriptional activator for efficient lytic induction therapy against EBV-associated epithelial cancers”的工作。该研究开发了一种新型合成转录激活剂mTZ3-LNP，即含有核苷修饰 mRNA 的脂质纳米颗粒，该mRNA 编码一种可以特异性激活EBV内源性 BZLF1基因的合成转录激活因子，从而有效诱导 EBV 阳性癌细胞的溶解，达到溶癌治疗的效果。

首先，研究者利用前期开发的基于CRISPR的RNA导向Casilio基因调控系统，设计sgRNA靶向EBV基因组内源裂解周期的主要调节基因BZLF1的启动子区域，从多个靶序列中筛选出最高效的序列以实现BZLF1内源转录激活，并在 EBV 阳性上皮癌中成功诱导细胞裂解。随后，鉴于通用递送载体的限制，研究团队基于转录激活因子样效应物（TALE）系统组装了一个体积较小的转录激活因子TZ3来代替体积较大的Casilio系统。

为了成功实现体内递送，研究者将编码TZ3的核苷修饰 mRNA（mTZ3）封装在脂质纳米颗粒 (LNP) 中。这些称为mTZ3-LNP的纳米颗粒能够成功转染EBV 阳性癌细胞系，并有效地诱导 BZLF1，以及早期和晚期EBV裂解蛋白的表达和Caspase-3的裂解，表明mTZ3-LNP可以成功诱导癌细胞凋亡。研究者通过对TZ3进行染色质免疫沉淀 (ChIP) 测序分析，证实 TZ3不存在与基因组的非特异性结合。此外，在对照实验中，mTZ3-LNP不影响 EBV 阴性细胞系 HK1 的转录组和表型，进一步证明mTZ3-LNP的特异性。

通过向植入 EBV 阳性癌细胞的 NOD-SCID 小鼠静脉注射 mTZ3-LNP，研究者成功诱导了小鼠模型中肿瘤异种移植物中早期和晚期裂解蛋白的表达，证明了体内 EBV相关胃癌和鼻咽癌肿瘤中的EBV裂解周期被有效诱导。研究者通过监测小鼠的肿瘤体积、小鼠体重变化、血清分析以及器官组织的病理学特征，明确了mTZ3-LNP 介导的溶癌疗法在 EBV 相关癌症临床前模型中的有效性和安全性。

综上所述，该研究成功开发了一种高效的mRNA 药物，用于针对 EBV 相关上皮癌的溶癌疗法，通过利用核苷修饰mRNA技术、非病毒递送策略和合成激活因子系统生产了mTZ3-LNP纳米药物，在多种EBV阳性上皮癌模型中激活内源性BZLF1从而达到肿瘤细胞的特异性裂解，并在小鼠模型里展示了一定的抗肿瘤作用以及安全性。

对标多种人类疾病的 mRNA 疗法正在不断发展，这种 EBV 靶向 mRNA 药物在体外和体内肿瘤模型中均具有有效且特异性的细胞毒作用，展现了mRNA药物对治疗恶性肿瘤的前景。

论文、新闻发布与媒体报道 Paper, press releases and media reports：

paper / 论文		1. Wu, M., Hau, P.-M., Li, L.*, Tsang, C.M., Yang, Y., Taghbalout, A., Chung, G.T.Y., Hui, S.Y., Tang, W.C., Jillette, N., Zhu, J.J., Lee, H.H.Y., Kong, E.L., Chan, M.S.A., Chan, J.Y.K., Ma, B.B.Y., Chen, M.-R., Lee, C., To, K.F., Cheng, A.W.#, Lo, K.-W.# (2024) Synthetic BZLF1-targeted transcriptional activator for efficient lytic induction therapy against EBV-associated epithelial cancers. Nature Communications 15:3729 doi: 10.1038/s41467-024-48031-8 (co-corresponding) IF=17.694 https://doi.org/10.1038/s41467-024-48031-8
		*equal contribution #co-corresponding

China Media / 中国媒体
1	中国科学院动物研究所	http://www.ioz.ac.cn/gb2018/xwdt/kyjz/202406/t20240611_7187213.html
2	Biotech 视界	https://mp.weixin.qq.com/s/18sFwM_Ne9PgRyzyOEJHEQ

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0	CUHK	https://www.cpr.cuhk.edu.hk/en/press/cu-medicine-developed-an-innovative-mrna-drug-for-treatment-of-nasopharyngeal-carcinoma/
0	CUHK Medicine press release	https://www.med.cuhk.edu.hk/press-releases/cu-medicine-developed-an-innovative-mrna-drug-for-treatment-of-nasopharyngeal-carcinoma
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35	文匯報 A04	https://www.wenweipo.com/a/202406/21/AP66748f1ce4b08d31ba67f62b.html
36	星島日報 A16	中大研發抗鼻咽癌藥物副作用較化療少
37	東方日報 A02	https://orientaldaily.on.cc/content/%E8%A6%81%E8%81%9E%E6%B8%AF%E8%81%9E/odn-20240621-0621_00176_024/%E4%B8%AD%E5%A4%A7%E6%96%B0%E6%A8%99%E9%9D%B6%E8%97%A5–%E5%8A%A9%E9%BC%BB%E5%92%BD%E7%99%8C%E6%82%A3%E8%80%85%E6%8A%97EB%E7%97%85%E6%AF%92
38	頭條日報 P21	與美國實驗室合作中大研新藥物治療鼻咽癌團隊:有望 4 年內展臨床試驗
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Albert Cheng, PhD 郑瑚博士

Professor
Institute of Zoology, CAS
研究员
中国科学院动物研究所