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lipid nanoparticle-mediated base-editing of the Hao1 gene achieves sustainable primary hyperoxaluria type 1 therapy in rats

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Science China life Sciences 2024年

作者： Dexin Zhang Rui Zheng Zhoutong Chen liren Wang Xi Chen Lei Yang Yanan Huo Shuming Yin Dan Zhang Jiaxin Huang Xingang Cui dali li Hongquan Geng Department of Urology Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Department of Urology Children's Hospital of Fudan University Shanghai Frontiers Science Center of Genome Editing and Cell Therapy Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University

Primary hyperoxaluria type 1(PH1) is a severe hereditary disease, leading to the accumulation of oxalate in multiple organs, particularly the kidney. Hydroxyacid oxidase 1(HAO1), a pivotal gene involved in oxalate production, is an approved target for the treatment of PH1. In this study, we demonstrated the discovery of several novel therapeutic sites of the Hao1 gene and the efficient editing of Hao1 c.290-2 A in vivo with lipid nanoparticles(LNP) delivered adenine base editing(ABE) mR NA. A single infusion of LNP-ABE resulted in a near-complete knockout of Hao1 in the liver, leading to the sustainable normalization of urinary oxalate(for at least 6 months) and complete rescue of the pathophysiology in PH1 rats. Additionally, a significant correlation between Hao1 editing efficiency and urinary oxalate levels was observed and over60% Hao1 editing efficiency was required to achieve the normalization of urinary oxalate in PH1 rats. These findings suggest that the LNPmediated base-editing of Hao1 c.290-2 A is an efficient and safe approach to PH1 therapy, highlighting its potential utility in clinical settings.

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CRISPR/Cas9 system： a powerful technology for in vivo and ex vivo gene therapy

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Science China(life Sciences) 2017年第5期60卷 468-475页

作者： Xiaohui Zhang liren Wang Mingyao liu dali li Shanghai Key Laboratory of Regulatory Biology institute of Biomedical Sciences and School of Life Sciences East China Normal University Shanghai 200241 China

CRISPR/Cas9 is a versatile genome-editing tool which is widely used for modifying the genome of both prokaryotic and eukaryotic organisms for basic research and applications. An increasing number of reports have demonstrated that CRISPR/Cas9-mediated genome editing is a powerful technology for gene therapy. Here, we review the recent advances in CRISPR/Cas9-mediated gene therapy in animal models via different strategies and discuss the challenges as well as future prospects.

关键词： CRISPR/Cas9 gene therapy in vivo ex vivo

Corrigendum to“Long-term correction of hemophilia B through CRISPR/Cas9 induced homology-independent targeted integration”[Journal of Genetics and Genomics(2022)49,1114-1126]

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Journal of Genetics and Genomics 2024年第5期51卷 578-578页

作者： Xi Chen Xuran Niu Yang liu Rui Zheng Lei Yang Jian Lu Shuming Yin Yu Wei Jiahao Pan Ahmed Sayed Xueyun Ma Meizhen liu Fengxiang Jing Mingyao liu Jiazhi Hu liren Wang dali li Shanghai Frontiers Science Center of Genome Editing and Cell Therapy Shanghai Key Laboratory of Regulatory BiologyInstitute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai 200241China The MOE Key Laboratory of Cell Proliferation and Differentiation Genome Editing Research CenterSchool of Life SciencesPeking-Tsinghua Center for Life SciencesPeking UniversityBeijing 100871China Xinhua Hospital Shanghai Jiao Tong University School of MedicineShanghai 200092China Biochemistry Laboratory Chemistry DepartmentFaculty of ScienceAssiut UniversityAssiut 71516Egypt Shanghai Turtle Technology Co. Shanghai 201900China

The authors regret that the grant number“21CJ1402200”in the Acknowledgments session should be replaced as“21JC1402200”.The corrected contents areprovided as follows.

关键词： CRISPR/Cas9 correction ledgment

Polyoxometalates-engineered hydrogen generation rate and durability of Pt/CNT catalysts from ammonia borane

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Journal of Energy Chemistry 2020年第2期29卷 142-148页

作者： Wenzhao Fu Chen Han dali li Wenyao Chen Jian Ji Gang Qian Weikang Yuan Xuezhi Duan Xinggui Zhou State Key Laboratory of Chemical Engineering East China University of Science and TechnologyShanghai 200237China Department of Chemical Engineering and Applied Chemistry University of TorontoToronto.Ontario M5S 3E5Canada

Heterogeneously catalyzed hydrolytic dehydrogenation of ammonia borane is a remarkable structure sensitive reaction. In this work, a strategy by using polyoxometalates(POMs) as the ligands is proposed to engineer the surface and electronic properties of Pt/CNT catalysts toward the enhanced hydrogen generation rate and durability. Three kinds of POMs, i.e., silicotungstic acid(STA), phosphotungstic acid(PTA)and molybdophosphoric acid(PMA), are comparatively studied, among which the STA shows positive effects on the catalytic activity and durability. A catalyst structure-performance relationship is established by a combination of kinetic and isotopic analyses with multiple characterization techniques, such as HAADF-STEM, EDS, Raman spectroscopy and XPS. It is shown that the STA compared to the other two POMs can increase the Pt binding energy and thus promote the reaction. The insights demonstrated here could open a new avenue for boosting the reaction by employing the POMs as the ligands to engineer the catalyst electronic properties.

关键词： Polyoxometalates Pt/CNT Electronic properties Hydrogen generation Durability

In vivo target protein degradation induced by PROTACs based on E3 ligase DCAF15

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Signal Transduction and Targeted Therapy 2020年第1期5卷 1324-1326页

作者： liang li Dazhao Mi Haixiang Pei Qiuhui Duan Xinyue Wang Wenbo Zhou Jianping Jin dali li Mingyao liu Yihua Chen Shanghai Key Laboratory of Regulatory Biology Joint Research Center for Translational MedicineECNU-Fengxian HospitalInstitute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai 200241China Joint Center for Translational Medicine Fengxian District Central HospitalShanghai 201499China MOE Key Laboratory for Biosystems Homeostasis&Protection and Innovation Center for Cell Signaling Network Life Sciences InstituteZhejiang UniversityHangzhouZhejiang 310058China

Dear Editor,As an emerging drug discovery paradigm,Proteolysis targeting chimeras(PROTACs)facilitate ubiquitination and degradation of the targets by cellular endogenous proteasome *** with traditional small molecular inhibitors,PROTACs work like enzymes and can operate with or without functional inhibition of the targets,which endows this strategy to degrade drug targets,especially useful for“undruggable”ones.

关键词： endogenous vivo system

WNT7A promotes tumorigenesis of head and neck squamous cell carcinoma via activating FZD7/JAK1/STAT3 signaling

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International Journal of Oral Science 2024年第1期16卷 85-96页

作者： Qingling Huang Yi Xiao Ting Lan Youguang Lu li Huang dali Zheng Department of Biochemistry and Molecular Biology School of Basic Medical SciencesFujian Medical UniversityFuzhouChina Fujian Key Laboratory of Oral Diseases School and Hospital of StomatologyFujian Medical UniversityFuzhouChina Department of Preventive Dentistry School and Hospital of StomatologyFujian Medical UniversityFuzhouChina Department of Dentistry The First Affiliated Hospital of Fujian Medical UniversityFuzhouChina

Wnt signaling are critical pathway involved in organ development, tumorigenesis, and cancer progression. WNT7A, a member of the Wnt family, remains poorly understood in terms of its role and the underlying molecular mechanisms it entails in head and neck squamous cell carcinoma (HNSCC). According to the Cancer Genome Atlas (TCGA), transcriptome sequencing data of HNSCC, the expression level of WNT7A in tumors was found to be higher than in adjacent normal tissues, which was validated using Real-time RT-PCR and immunohistochemistry. Unexpectedly, overexpression of WNT7A did not activate the canonical Wnt-β-catenin pathway in HNSCC. Instead, our findings suggested that WNT7A potentially activated the FZD7/JAK1/STAT3 signaling pathway, leading to enhanced cell proliferation, self-renewal, and resistance to apoptosis. Furthermore, in a patient-derived xenograft (PDX) tumor model, high expression of WNT7A and phosphorylated STAT3 was observed, which positively correlated with tumor *** findings underscore the significance of WNT7A in HNSCC progression and propose the targeting of key molecules within the FZD7/JAK1/STAT3 pathway as a promising strategy for precise treatment of HNSCC.

关键词： WNT squamous tumorigenesis

Gene editing and its applications in biomedicine

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Science China(life Sciences) 2022年第4期65卷 660-700页

作者： Guanglei li Xiangyang li Songkuan Zhuang liren Wang Yifan Zhu Yangcan Chen Wen Sun Zeguang Wu Zhuo Zhou Jia Chen Xingxu Huang Jin Wang dali li Wei li Haoyi Wang Wensheng Wei School of life Science and Technology ShanghaiTech UniversityShanghai201210China Department of Clinical Laboratory Shenzhen Institute of Translational MedicineThe First Affiliated Hospital of Shenzhen UniversityShenzhen Second People’s HospitalShenzhen518035China Shanghai Frontiers Science Research Base of Genome Editing and Cell Therapy Shanghai Key Laboratory of Regulatory BiologySchool of Life SciencesEast China Normal UniversityShanghai200241China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing100101China University of Chinese Academy of Sciences Beijing100049China Institute for Stem Cell and Regenerative Medicine Chinese Academy of SciencesBeijing100101China Biomedical Pioneering Innovation Center Beijing Advanced Innovation Center for GenomicsPeking-Tsinghua Center for Life SciencesPeking University Genome Editing Research CenterState Key Laboratory of Protein and Plant Gene ResearchSchool of Life SciencesPeking UniversityBeijing100871China Gene Editing Center School of Life Science and TechnologyShanghaiTech UniversityShanghai201210China Bejing Institute for Stem Cell and Regenerative Medicine Beijing100101China HIT Center for life Sciences Harbin Institute of TechnologyHarbin150001China

The steady progress in genome editing, especially genome editing based on the use of clustered regularly interspaced short palindromic repeats(CRISPR) and programmable nucleases to make precise modifications to genetic material, has provided enormous opportunities to advance biomedical research and promote human health. The application of these technologies in basic biomedical research has yielded significant advances in identifying and studying key molecular targets relevant to human diseases and their treatment. The clinical translation of genome editing techniques offers unprecedented biomedical engineering capabilities in the diagnosis, prevention, and treatment of disease or disability. Here, we provide a general summary of emerging biomedical applications of genome editing, including open challenges. We also summarize the tools of genome editing and the insights derived from their applications, hoping to accelerate new discoveries and therapies in biomedicine.

关键词： gene editing CRISPR high-throughput functional genomics diagnostics animal model therapeutics

Long-term amelioration of an early-onset familial atrial fibrillation model with AAV-mediated in vivo gene therapy

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Fundamental Research 2022年第6期2卷 829-835页

作者： Handan Hu liren Wang Huiying li Hailing li Xi Chen Wenhui Peng Jun Wang Yongxiang Zhao Mingyao liu dali li Shanghai Frontiers Science Center of Genome Editing and Cell Therapy Shanghai Key Laboratory of Regulatory BiologyInstitute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai 200241China Southern Medical University Affiliated Fengxian Hospital Shanghai 201499China The Department of Cardiology Shanghai Tenth People's HospitalSchool of MedicineTongji UniversityShanghai 200072China Department of Pediatrics McGovern Medical SchoolThe University of Texas Health Science Center at HoustonHoustonTX 77030United States National Center for International Biotargeting Theranostics Guangxi Key Laboratory of Biotargeting TheranosticsCollaborative Innovation Center for Targeting Tumor TheranosticsGuangxi Medical UniversityGuangxi 530021China

Atrial fibrillation(AF)is a common cardiac disease with high prevalence in the general *** a mild manifestation at the onset stage,it causes serious consequences,including sudden death,when the disease progresses to the late *** available treatments of AF focus on symptom management or alleviation,due to a lack of fundamental knowledge and the fact that considerable variations of AF *** the popularisation of the next-generation sequencing technology,several causal genetic factors,including MYL4,have been discovered to contribute to AF,giving hope to developing its gene *** this study,we attempted to treat a previously established rat AF model,which carried Myl4E11K/E11K loss of function mutation,via overexpression of exogenous wild-type Myl4 by AAV9 *** results showed that delivery of Myl4 expressing AAV9 to postnatal rat models rescued the symptoms of AF,indicating the therapeutic potential that early gene therapy intervention can achieve long-term effects in treating cardiac arrhythmias caused by gene mutations.

关键词： Atrial fibrillation Gene therapy AAV 9Myl4 Genetic disorder

Generation of obese rat model by transcription activator-like effector nucleases targeting the leptin receptor gene

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Science China(life Sciences) 2017年第2期60卷 152-157页

作者： Yuting Chen Wenqing Lu Na Gao Yi Long Yanjiao Shao Meizhen liu Huaqing Chen Shixin Ye Xueyun Ma Mingyao liu dali li Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University Shanghai 200241 China Ecole Normale Supérieure Institut de Biologie de l' Ecole Normale Supérieure Institut National de la Santé et de la Recherche Médicale U1024 Centre National de la Recherche Scientifique Unité Mixte de Recherche 8197 Paris F-75005 France Institute of Biosciences and Technology Department of Molecular and Cellular Medicine Texas A&M University Health Science Center Houston Texas 77030 USA

The laboratory rat is a valuable mammalian model organism for basic research and drug discovery. Here we demonstrate an efficient methodology by applying transcription activator-like effector nucleases(TALENs) technology to generate Leptin receptor(Lepr) knockout rats on the Sprague Dawley(SD) genetic background. Through direct injection of in vitro transcribed m RNA of TALEN pairs into SD rat zygotes, somatic mutations were induced in two of three resulting pups. One of the founders carrying bi-allelic mutation exhibited early onset of obesity and infertility. The other founder carried a chimeric mutation which was efficiently transmitted to the progenies. Through phenotyping of the resulting three lines of rats bearing distinct mutations in the Lepr locus, we found that the strains with a frame-shifted or premature stop codon mutation led to obesity and metabolic disorders. However, no obvious defect was observed in a strain with an in-frame 57 bp deletion in the extracellular domain of Lepr. This suggests the deleted amino acids do not significantly affect Lepr structure and function. This is the first report of generating the Lepr mutant obese rat model in SD strain through a reverse genetic approach. This suggests that TALEN is an efficient and powerful gene editing technology for the generation of disease models.

关键词： TALENs Lepr knockout rat germ-line transmission