Preparation of LC09-PPC-CRISPR/Cas9 delivery system


遞送系統LC09-PPC-CRISPR/Cas9的製備流程

Date: 09 Nov 2017 (Thursday)

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Chinese medicine scholars develop innovative targeted delivery system for treating osteosarcoma

中醫學者成功研發在體靶向基因編輯遞送系統 有助治療惡性骨肉瘤

Chinese Medicine scholars have succeeded in developing a novel targeted delivery system for CRISPR/Cas9 to achieve therapeutic genome editing of VEGFA in osteosarcoma (OS). Their research paper entitled “Tumor cell-targeted delivery of CRISPR/Cas9 by aptamer-functionalised lipopolymer for therapeutic genome editing of VEGFA in osteosarcoma” was recently published in the internationally renowned academic journal Biomaterials. (https://www.ncbi.nlm.nih.gov/pubmed/28938163)

CRISPR/Cas9 is a budding genome editing technology which holds tremendous promise for cancer treatment. However, a major bottleneck for achieving the therapeutic potential of CRISPR/Cas9 is the lack of an in vivo targeted delivery system. The HKBU team has achieved a breakthrough in the search for an answer to the crux of the above mentioned problem and developed an aptamer-functionalised delivery system for CRISPR/Cas9 with the treatment of OS as a research target.

The research team is led by Professor Lyu Aiping, Dean of the School of Chinese Medicine (SCM), and Professor Zhang Ge, Director of Technology Development Division and Associate Director of Teaching and Research Division of SCM.

Professor Zhang Ge said: “OS, a very common primary malignant bone tumor in children and adolescents, is mainly treated by surgery and chemotherapy but the five-year post-surgery survival rate is a mere 5% to 20%. Aptamers which are single-stranded oligonucleotides and could specifically recognise target cells have been widely used for in vivo targeted delivery of therapeutics. VEGFA has been reported to be a novel therapeutic target for OS.”

Professor Lyu Aiping said: “The tumor-specific aptamers, when conjugated with PPC polymers encapsulating CRISPR/Cas9, may facilitate therapeutic genome editing in tumors.”

In the experiments using a mouse model, the aptamer facilitated selective distribution of CRISPR/Cas9 in both orthotopic OS and lung metastasis, leading to effective in vivo VEGFA genome editing, inhibited orthotopic OS malignancy and lung metastasis, as well as reduced angiogenesis and bone lesion with no detectable toxicity. The research facilitated clinical application of CRISPR/Cas9 in tumor treatment.

Other researchers who participated in the research include SCM’s Post-doctoral Research Fellow Dr Liang Chao, Research Assistant Professor Dr Li Fangfei, PhD student Ms Wang Luyao, Dr Wang Chao from the research team of Dr Zhu Hailong of SCM, and Dr Zhang Zongkang of the research team of Dr Zhang Baoting of the School of Chinese Medicine, The Chinese University of Hong Kong.

中醫藥研究團隊成功研發在體靶向骨肉瘤基因編輯遞送系統,有助治療骨肉瘤。他們的論文「基於適配子功能化的腫瘤細胞特異性CRISPR/Cas9遞送系統實現骨肉瘤VEGFA基因編輯」近日獲得生物材料範疇的國際權威學術雜誌《Biomaterials》刊登 (https://www.ncbi.nlm.nih.gov/pubmed/28938163)。

CRISPR/Cas9是一種新興的基因編輯技術,已被用於腫瘤的分子機制和治療靶點的研究,但是一直缺乏一種能夠在體靶向腫瘤的基因編輯的遞送系統,限制了該技術的臨床轉化。浸大研究團隊針對問題的癥結,努力研究以骨肉瘤治療為研究靶點,成功研發了適配子功能化的CRISPR/Cas9遞送系統。

研究團隊由中醫藥學院院長呂愛平教授與研究開發部主任兼教學科研部副主任張戈教授率領。張戈教授說:「骨肉瘤是兒童及青少年最為常見的原發性惡性骨腫瘤,目前的治療方法是以手術與化療為主,但手術後五年存活率僅為5%至20%。適配子(Aptamer)是一類具有三維結構的單鏈寡核苷酸,可以與特定的細胞結合,已被廣泛應用於藥物的靶向遞送。VEGFA基因已被證實為骨肉瘤治療的潛在靶點。」

呂愛平教授說:「我們把識別腫瘤細胞的適配子作為靶向配體,與包裝了CRISPR/Cas9的聚合生物材料偶聯在一起,有利於實現腫瘤內的治療性基因編輯。」

在以小鼠模型進行的實驗中,該遞送系統可加速CRISPR/Cas9在小鼠模型骨肉瘤和肺轉移病灶的特異性聚集,促進腫瘤細胞的VEGFA基因編輯,抑制腫瘤惡化,降低肺轉移,減少腫瘤組織血管增生,抑制骨破壞,並無明顯毒性。該CRISPR/Cas9靶向遞送系統加速了基因編輯策略在腫瘤治療領域的臨床轉化應用。
   
參與研究工作的還有浸大博士後研究學人梁超博士、研究助理教授李芳菲博士、博士研究生王璐瑤同學、中醫藥學院祝海龍博士研究團隊成員王超博士,以及香港中文大學中醫學院張保亭教授研究團隊的張宗康博士。