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CRISPR/Cas9-mediated correction of human genetic disease

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Science China(Life Sciences) 2017年第5期60卷 447-457页

作者： Ke Men Xingmei Duan Zhiyao He Yang Yang shaohua yao Yuquan Wei State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy West China Hospital Sichuan University Chengdu 610041 China Individualized Medication Key Laboratory of Sichuan Province Department of Pharmacy Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital Sichuan Translational Medicine Hospital Chengdu 610072 China Department of Pharmacy State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 China

The clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated(Cas) protein 9 system(CRISPR/Cas9) provides a powerful tool for targeted genetic editing. Directed by programmable sequence-specific RNAs,this system introduces cleavage and double-stranded breaks at target sites precisely. Compared to previously developed targeted nucleases, the CRISPR/Cas9 system demonstrates several promising advantages, including simplicity, high specificity,and efficiency. Several broad genome-editing studies with the CRISPR/Cas9 system in different species in vivo and ex vivo have indicated its strong potential, raising hopes for therapeutic genome editing in clinical settings. Taking advantage of non-homologous end-joining(NHEJ) and homology directed repair(HDR)-mediated DNA repair, several studies have recently reported the use of CRISPR/Cas9 to successfully correct disease-causing alleles ranging from single base mutations to large insertions. In this review, we summarize and discuss recent preclinical studies involving the CRISPR/Cas9-mediated correction of human genetic diseases.

关键词： CRISPR/Cas9 genome editing genetic disease gene therapy

DnaQ mediates directional spacer acquisition in the CRISPR-Cas system by a time-dependent mechanism

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The Innovation 2023年第5期4卷 78-86页

作者： Dongmei Tang Tingting Jia Yongbo Luo Biqin Mou Jie Cheng Shiqian Qi shaohua yao Zhaoming Su Yamei Yu Qiang Chen Department of Urology.State Key Laboratory of Biotherapy West China HospitalSichuan UniversityChengdu 610041China Department of Biotherapy Cancer Center and State Key Laboratory of BioherapyWest China HospitalSichuan UniversiyChengdu 610041China Precision Medicine Center Precision Medicine Key Laboratory of Sichuan ProvinceWest China HospitalSichuan UniversityChengdu 610041China

In the spacer acquisition stage of CRISPR-Cas immunity,spacer orientation and protospacer adjacent motif(PAM)removal are two prerequisites for functional spacer ***4 has been implicated in both processing the prespacer and determining the spacer *** Cas4-lacking systems,host 3′–5′DnaQ family exonucleases were recently reported to play a Cas4-like ***,the molecular details of DnaQ functions remain ***,we characterized the spacer acquisition of the adaptation module of the Streptococcus thermophilus type I-E system,in which a DnaQ domain naturally fuses with *** presented X-ray crystal structures and cryo-electron microscopy structures of this adaptation *** biochemical data showed that DnaQ trimmed PAM-containing and PAM-deficient overhangs with different *** on these results,we proposed a time-dependent model for DnaQ-mediated spacer acquisition to elucidate PAM removal and spacer orientation determination in Cas4-lacking CRISPR-Cas systems.

关键词： details media directional

WT-PE:Prime editing with nuclease wild-type Cas9 enables versatile large-scale genome editing

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Signal Transduction and Targeted Therapy 2022年第5期7卷 1756-1763页

作者： Rui Tao Yanhong Wang Yun Hu yaoge Jiao Lifang Zhou Lurong Jiang Li Li Xingyu He Min Li Yamei Yu Qiang Chen shaohua yao From laboratory of Biotherapy National Key Laboratory of BiotherapyCancer CenterWest China HospitalSichuan universityRenmin Nanlu 17Chengdu 610041 SichuanChina

Large scale genomic aberrations including duplication,deletion,translocation,and other structural changes are the cause of a subtype of hereditary genetic disorders and contribute to onset or progress of *** current prime editor,PE2,consisting of Cas9-nickase and reverse transcriptase enables efficient editing of genomic deletion and insertion,however,at small ***,we designed a novel prime editor by fusing reverse transcriptase(RT)to nuclease wild-type Cas9(WT-PE)to edit large genomic fragment.

关键词： Cas9 nuclease editor

Dual-AAV split prime editor corrects the mutation and phenotype in mice with inherited retinal degeneration

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Signal Transduction and Targeted Therapy 2023年第3期8卷 1186-1197页

作者： Kaiqin She Yi Liu Qinyu Zhao Xiu Jin Yiliu Yang Jing Su Ruiting Li Li Song Jianlu Xiao shaohua yao Fang Lu Yuquan Wei Yang Yang Department of Ophthalmology West China HospitalSichuan UniversityChengduSichuanChina State Key Laboratory of Biotherapy and Cancer Center West China HospitalSichuan University and Collaborative Innovation CenterChengduSichuanChina

The prime editor(PE)can edit genomes with almost any intended changes,including all 12 possible types of base substitutions,small insertions and deletions,and their combinations,without the requirement for double strand breaks or exogenous donor *** demonstrates the possibility of correcting a variety of disease-causing mutations and might expand the therapeutic application of gene *** this study,PE was optimized based on a dual-adeno-associated virus(AAV)split-intein system in vitro by screening different split sites and split *** found that splitting PE before amino acid 1105(Ser)of SpCas9 with Rma intein resulted in the highest on-target *** orientations of pegRNA and nicking sgRNA in the AAV vector were further *** test the in vivo performance of the optimized dual-AAV split-PE3,it was delivered by subretinal injection in rd12 mice with inherited retinal disease Leber congenital *** prime editors corrected the pathogenic mutation with up to 16%efficiency in a precise way,with no detectable off-target edits,restored RPE65 expression,rescued retinal and visual function,and preserved *** findings establish a framework for the preclinical development of PE and motivate further testing of PE for the treatment of inherited retinal diseases caused by various mutations.

关键词： editor degeneration precise

Programmable double-unlock nanocomplex self-supplies phenylalanine ammonia-lyase for precise phenylalanine deprivation of tumors

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Chinese Chemical Letters 2024年第8期35卷 455-459页

作者： Chunqing Ou Meijia Xiao Xinyue Zheng Xianzhou Huang Suleixin Yang Yingying Leng Xiaowei Liu Xiuqi Liang Linjiang Song Yanjie You shaohua yao Changyang Gong Department of Biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoAvenida da UniversidadeTaipaMacao 999087China School of Medical and Life Sciences Chengdu University of Traditional Chinese MedicineChengdu 611137China Department of Gastroenterology People’s Hospital of Ningxia Hui Autonomous RegionYinchuan 750002China

Essential amino acids(EAAs)deprivation is a potential antitumor approach because EAAs are critical for tumor *** efficiently inhibit tumor growth,continuous deprivation of EAAs is required,how-ever,continuous deprivation without precise control will introduce toxicity to normal ***,a programmable double-unlock nanocomplex(ROCK)was prepared,which could self-supply phenylalanine ammonia-lyase(PAL)to tumor cells for phenylalanine(Phe)*** was double-locked in physiological conditions when administered *** ROCK actively targeted to tumor cells by integrinαvβ3/5 and CD44,ROCK was firstly unlocked by cleavage of protease on tumor cell membrane,exposing CendR and R8 to enhance ***,hyaluronic acid was digested by hyaluronidase overexpressed in endo/lysosome of tumor cells,in which ROCK was secondly unlocked,resulting in pro-moting endo/lysosome escape and PAL plasmid(pPAL)*** pPAL could sustainably express PAL in host tumor cells until the self-supplied PAL precisely and successfully deprived Phe,thereby block-ing the protein synthesis and killing tumor cells ***,our precise Phe deprivation strategy effectively inhibited tumor growth with no observable toxicity to normal cells,providing new insights to efficiently remove intratumoral nutrition for cancer therapy.

关键词： Programmable double-unlock Essential amino acids deprivation Phenylalanine ammonia-lyase Self-supply Gene therapy

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含区间参数的战场资源动态调度模型及算法

系统工程理论与实践 2017年第4期37卷 1080-1088页

作者：孙昱姚佩阳张少华肖瑶空军工程大学信息与导航学院中国人民解放军95084部队

战场资源调度是作战指挥领域研究的热点.首先描述了战场资源调度问题,分析了战场资源动态调度需求,在此基础上建立了包含区间参数的战场资源动态调度模型.然后设计了三种不同的贪心策略,分别为基本贪心策略、双重贪心策略和一致贪心策略... 详细信息

战场资源调度是作战指挥领域研究的热点.首先描述了战场资源调度问题,分析了战场资源动态调度需求,在此基础上建立了包含区间参数的战场资源动态调度模型.然后设计了三种不同的贪心策略,分别为基本贪心策略、双重贪心策略和一致贪心策略,提出了模型求解的混合贪心算法.最后结合联合作战算例进行了仿真验证,结果表明本文方法可行优越,能应用于不确定性的战场环境中.

关键词：战场资源动态调度区间参数贪心算法

Kzp Regulates the Transcription of gata2 and pu.1 during Primitive Hematopoiesis in Zebrafish Embryos

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Journal of Genetics and Genomics 2012年第9期39卷 463-471页

作者： Fang Liu shaohua yao Ting Zhang Chun Xiao Yanna Shang Jin Liu Xianming Mo Laboratory of Stem Cell Biology State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 China

Kaiso zinc finger-containing protein（Kzp）,a maternally-derived transcription factor,controls dorsoventral patterning during zebrafish ***,we uncovered a new function for Kzp in zebrafish embryonic primitive *** depletion of kzp led to defects in primitive hematopoiesis including the development of the erythroid and myeloid *** the other hand,overexpression of kzp caused the ectopic expression of gata1,gata2,and *** immunoprecipitation assays revealed that Kzp protein directly binds to gata1,gata2,and pu.1 ***,the ectopic expression of gatal was able to rescue the erythroid,but not the myeloid lineage in kzp-depleted zebrafish ***1 expression controlled by Kzp was dependent on gatal during primitive *** results indicate that Kzp is a critical transcriptional factor for the expression of gata2 and pu.1 to modulate primitive hematopoiesis.

关键词： kzp Hematopoiesis Erythropoiesis Myelopoiesis Zebrafish

Efficient Gene Targeting in Zebrafish Mediated by a Zebrafish-Codon-Optimized Cas9 and Evaluation of Off-Targeting Effect

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Journal of Genetics and Genomics 2014年第1期41卷 43-46页

作者： Da Liu Zhanxiang Wang An Xiao Yutian Zhang Wenyuan Li yao Zu shaohua yao Shuo Lin Bo Zhang Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education College of Life Sciences Peking University Laboratory of Chemical Genomics School of Chemical Biology and Biotechnology Peking University Shenzhen Graduate School Department of Molecular Cell and Developmental Biology University ofCalifornia

Targeted genome modifications with the Cas9/gRNA system derived from the clustered regularly interspaced short palin- dromic repeat/CRISPR-associated （CRISPR/Cas） system have been successfully used in cultured human cells as well as in most model organisms, including zebrafish （Danio rerio）, mouse, and fruit fly （Chang et al., 2013; Cong et al., 2013; Gratz et al., 2013; Hwang et al., 2013; Jao et al., 2013; Shen et al., 2013; Wei et al., 2013）. Its application in zebrafish is particu- larly attractive due to the ease of handling this organism and the simple application of this method by direct injection of Cas9/ gRNA. However, the information about its specificity in this organism is very limited and needs further evaluation. In addition, it is conceivable that a Cas9 mRNA optimized for zebrafish codon preference could enhance its activity.

关键词： Efficient Gene Targeting in Zebrafish Mediated by a Zebrafish-Codon-Optimized Cas9 and Evaluation of Off-Targeting Effect

ApoA-ll directs zebrafish morphogenetic movements during gastrulation by regulating nucleus division in yolk syncytial layer

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ApoA-ll directs zebrafish morphogenetic movements during gas...