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AAV-mediated gene therapies by miniature gene editing tools

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Science China Life Sciences 2024年

作者： Xiangfeng Kong Tong Li Hui Yang Shanghai Institute of Materia Medica Chinese Academy of Sciences Institute of neuroscience Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of Sciences HuidaGene Therapeutics Co. Ltd. Shanghai Center for Brain Science and Brain-Inspired Technology

The advent of CRISPR-Cas has revolutionized precise gene editing. While pioneering CRISPR nucleases like Cas9 and Cas12 generate targeted DNA double-strand breaks(DSB) for knockout or homology-directed repair, next generation CRISPR technologies enable gene editing without DNA DSB. Base editors directly convert bases, prime editors make diverse alterations, and dead Cas-regulator fusions allow nuanced control of gene expression, avoiding potentially risks like translocations. Meanwhile, the discovery of diminutive Cas12 orthologs and Obligate Mobile Element-Guided Activity(OMEGA) nucleases has overcome cargo limitations of adeno-associated viral vectors, expanding prospects for in vivo therapeutic delivery. Here, we review the ever-evolving landscape of cutting-edge gene editing tools, focusing on miniature Cas12 orthologs and OMEGA effectors amenable to single AAV packaging. We also summarize CRISPR therapies delivered using AAV vectors, discuss challenges such as efficiency and specificity, and look to the future of this transformative field of in vivo gene editing enabled by AAV vectors delivery.

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Learning of Concepts: A Review of Relevant Advances Since 2010 and Its Inspirations for Teaching

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Journal of Contemporary Educational Research 2024年第6期8卷 1-15页

作者： Zhong Wang Institute of Clinical Education Beijing Doers Education Consulting Co.Ltd.China

This article reviews the psychological and neuroscience achievements in concept learning since 2010 from the perspectives of individual learning and social learning,and discusses several issues related to concept learning,including the assistance of machine learning about concept *** terms of individual learning,current evidence shows that the brain tends to process concrete concepts through typical features(shared features);and for abstract concepts,semantic processing is the most important cognitive *** terms of social learning,interpersonal neural synchrony(INS)is considered the main indicator of efficient knowledge transfer(such as teaching activities between teachers and students),but this phenomenon only broadens the channels for concept sources and does not change the basic mode of individual concept ***,this article argues that the way the human brain processes concepts depends on the concept’s own characteristics,so there are no“better”strategies in teaching,only more“suitable”strategies.

关键词： Concept learning Concrete concepts Abstract concepts Interpersonal neural synchrony Machine learning Review

Amyloid-beta and tau protein beyond Alzheimer's disease

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Neural Regeneration Research 2024年第6期19卷 1262-1276页

作者： Morteza Abyadeh Vivek Gupta Joao A.Paulo Arezoo Gohari Mahmoudabad Sina Shadfar Shahab Mirshahvaladi Veer Gupta Christine T.O.Nguyen David I.Finkelstein Yuyi You Paul A.Haynes Ghasem H.Salekdeh Stuart L.Graham Mehdi Mirzaei ProGene Technologies Pty ltd. SydneyNSWAustralia Department of Clinical Medicine Faculty of MedicineHealth and Human SciencesMacquarie Medical SchoolMacquarie UniversityMacquarie ParkNorth RydeSydneyNSWAustralia Department of Cell Biology Harvard Medical SchoolBostonMAUSA School of Medicine Deakin UniversityGeelongVICAustralia Department of Optometry and Vision Sciences School of Health SciencesFaculty of Medicine Dentistry and Health SciencesUniversity of MelbourneParkvilleVICAustralia The Florey Institute of neuroscience and Mental Health The University of MelbourneParkvilleVICAustralia School of Natural Sciences Macquarie UniversityMacquarie ParkNSWAustralia

The aggregation of amyloid-beta peptide and tau protein dysregulation are implicated to play key roles in Alzheimer's disease pathogenesis and are considered the main pathological hallmarks of this devastating ***,these two proteins are produced and expressed within the normal human ***,under pathological conditions,abnormal expression,posttranslational modifications,conformational changes,and truncation can make these proteins prone to aggregation,triggering specific disease-related *** studies have indicated associations between aberrant behavior of amyloid-beta and tau proteins and various neurological diseases,such as Alzheimer's disease,Parkinson's disease,and amyotrophic lateral sclerosis,as well as retinal neurodegenerative diseases like Glaucoma and age-related macular ***,these proteins have been linked to cardiovascular disease,cancer,traumatic brain injury,and diabetes,which are all leading causes of morbidity and *** this comprehensive review,we provide an overview of the connections between amyloid-beta and tau proteins and a spectrum of disorders.

关键词： amyloid-beta cancer cardiovascular diseases diabetes neurodegeneration Tau traumatic brain injury

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Alleviated mucosal and neuronal damage in a rat model of Crohn's disease

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World Journal of Gastroenterology 2014年第44期20卷 16690-16697页

作者： Petra Talapka Lajos István Nagy Alexandr. Pál Marietta Zita Poles Anikó Berkó Mária Bagyánszki László Géza Puskás éva Fekete Nikolett Bódi Department of Physiology Anatomy and Neuroscience Faculty of Sciences and Informatics University of Szeged Avidin ltd.

AIM:To establish a rat model suitable to investigate the repetitive relapsing inflammations(RRI)characteristic to Crohn’s ***:Colitis was induced by 2,4,6-trinitrobenzenesulfonic acid(TNBS).RRI were mimicked by repeating administrations of *** samples were taken from control,once,twice and three times treated rats from the inflamed and adjacent non-inflamed colonic segments at different timepoints during the acute intestinal *** means of the ulcerated area were measured to evaluate the macroscopic mu-cosal *** density of myenteric neurons was determined on whole mounts by Hu C/Hu D *** oxygenase-1(HO-1)expression was evaluated by molecular biological ***:TNBS-treated rats displayed severe colitis,but the mortality was negligible,and an increase of body weight was characteristic throughout the experimental *** widespread loss of myenteric neurons,and marked but transient HO-1 up-regulation were demonstrated after the first TNBS *** repeated doses the length of the recovery time and extent of the ulcerous colonic segments were markedly decreased,and the neuronal loss was on a smaller scale and was limited to the inflamed ***-1 m RNA level was notably greater than after a single dose and overexpression was sustained throughout the timepoints ***,the HO-1protein up-regulation after the second TNBS treatment proved to be *** the third treatment HO-1 protein expression could not be ***:Experimentally provoked RRI may exert a protective preconditioning effect against the mucosal and neuronal *** persistent up-regulation of HO-1 m RNA expression may correlate with this.

关键词： Crohn's disease Experimental rat model Heme oxygenase-1 Myenteric neurons Repetitive re-lapsing inflammation

Enhanced Beta2-band Oscillations Denote Auditory Hallucination in Schizophrenia Patients and a Monkey Model of Psychosis

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neuroscience Bulletin 2024年第3期40卷 325-338页

作者： Shuo Ma Tianzhen Chen Wenjun Jia Jie Liu Shihan Ding Puzhe Li Hong Gan Dapeng Zhang Shuxin Shao Mu-Ming Poo Min Zhao Bomin Sun Jian Jiang Department of Neurosurgery Ruijin HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200020China Shanghai Mental Health Center Shanghai Jiao Tong University School of MedicineShanghai200030China Shanghai Center for Brain Science and Brain-inspired Technology Lingang LaboratoryShanghai201602China University of California at Berkeley BerkeleyCA94720USA School of Life Science and Technology ShanghaiTech UniversityShanghai201210China Institute of neuroscience CAS Center for Excellence in Brain Science and Intelligence TechnologyCAS Key Laboratory of Primate NeurobiologyState Key Laboratory of NeuroscienceChinese Academy of SciencesShanghai200031China Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology Lingang LaboratoryShanghai201210China Fuyang Third People’s Hospital Fuyang Mental Health CenterFuyang236052China Shanghai Key Laboratory of Psychotic Disorders Shanghai200030China Institute of Psychological and Behavioral Science Shanghai Jiao Tong UniversityShanghai200030China Shanghai Quanlan Technology Co. LtdShanghai201602China

An electroencephalographic(EEG)signature of auditory hallucinations(AHs)is important for facilitating the diagnosis and treatment of AHs in *** recorded EEG from 25 schizophrenia patients with recurrent *** the period of AHs,EEG recordings exhibited significantly elevated beta2-band power in the temporal region,as compared to those recorded in the absence of AHs or during stimulation with verbal *** further generated methamphetamine-treated rhesus monkeys exhibiting psychosis-like behaviors,including repetitive sudden searching actions in the absence of external intrusion,suggesting the occurrence of *** EEG beta2-band power in the temporal region of these monkeys was enhanced immediately after methamphetamine treatment and positively correlated with the frequency of sudden searching ***,the enhancement of temporal beta2-band oscillations represents a signature for AHs in both patients and a monkey model of psychosis,and this monkey model can be used for developing closed-loop neuromodulation approaches for the treatment of refractory AHs in schizophrenia.

关键词： Schizophrenia Auditory hallucinations Non-human primate Methamphetamine Electroencephalography

Structural and molecular features of intestinal strictures in rats with Crohn's-like disease

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World Journal of Gastroenterology 2016年第22期22卷 5154-5164页

作者： Petra Talapka Anikó Berkó Lajos István Nagy Lalitha Chandr.kumar Mária Bagyánszki László Géza Puskás éva Fekete Nikolett Bódi Department of Physiology Anatomy and Neuroscience Faculty of Sciences and Informatics University of Szeged H-6726 Szeged Hungary Avidin ltd. H-6726 Szeged Hungary

AIM: To develop a new rat model we wanted to gain a better understanding of stricture formation in Crohn’s disease (CD).METHODS: Chronic colitis was induced locally by the administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS). The relapsing inflammation characteristic to CD was mimicked by repeated TNBS treatments. Animals were randomly divided into control, once, twice and three times TNBS-treated groups. Control animals received an enema of saline. Tissue samples were taken from the strictured colonic segments and also adjacent proximally and distally to its 60, 90 or 120 d after the last TNBS or saline administrations. The frequency and macroscopic extent of the strictures were measured on digital photographs. The structural features of strictured gut wall were studied by light- and electron microscopy. Inflammation related alterations in TGF-beta 2 and 3, matrix metalloproteinases 9 (MMP9) and TIMP1 mRNA and protein expression were determined by quantitative real-time PCR and western blot analysis. The quantitative distribution of caspase 9 was determined by post-embedding ***: Intestinal strictures first appeared 60 d after TNBS treatments and the frequency of them increased up to day 120. From day 90 an intact lamina epithelialis, reversible thickening of lamina muscularis mucosae and irreversible thickening of the muscularis externa were demonstrated in the strictured colonic segments. Nevertheless the morphological signs of apoptosis were frequently seen and excess extracellular matrix deposition was recorded between smooth muscle cells (SMCs). Enhanced caspase 9 expression on day 90 in the SMCs and on day 120 also in myenteric neurons indicated the induction of apoptosis. The mRNA expression profile of TGF-betas after repeated TNBS doses was characteristic to CD, TGF-beta 2, but not TGF-beta 3 was up-regulated. Overexpression of MMP9 and down-regulation of TIMP1 were demonstrated. The progressive increase in the amount

关键词： Crohn’ s disease Rat model TGF-beta Intestinal strictures MMP9 TIMP1

Programmable deaminase-free base editors for G-to-Y conversion by engineered glycosylase

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National Science Review 2023年第8期10卷 78-87页

作者： Huawei Tong Nana Liu Yinghui Wei Yingsi Zhou Yun Li Danni Wu Ming Jin Shuna Cui Hengbin Li Guoling Li Jingxing Zhou Yuan Yuan Hainan Zhang Linyu Shi Xuan Yao Hui Yang HuidaGene Therapeutics Co. Ltd. Department of Neurology and Institute of Neurology of First Affiliated Hospital Institute of Neuroscience and Fujian Key Laboratory of Molecular Neurology Fujian Medical University Institute of neuroscience Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of Sciences Shanghai Center for Brain Science and Brain-Inspired Intelligence

Current DNA base editors contain nuclease and DNA deaminase that enables deamination of cytosine(C)or adenine(A), but no method for guanine(G) or thymine(T) editing is available at present. Here we developed a deaminase-free glycosylase-based guanine base editor(gGBE) with G editing ability, by fusing Cas9 nickase with engineered N-methylpurine DNA glycosylase protein(MPG). By several rounds of MPG mutagenesis via unbiased and rational screening using an intron-split EGFP reporter, we demonstrated that gGBE with engineered MPG could increase G editing efficiency by more than 1500 ***, this gGBE exhibited high base editing efficiency(up to 81.2%) and high G-to-T or G-to-C(i.e. G-to-Y) conversion ratio(up to 0.95) in both cultured human cells and mouse embryos. Thus, we have provided a proof-of-concept of a new base editing approach by endowing the engineered DNA glycosylase the capability to selectively excise a new type of substrate.

关键词： glycosylase base excision repair base editor depurination deaminase-free transversion

Apoptosis is not an invariable component of in vitro models of cortical cerebral ischaemia

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Cell Research 2004年第3期14卷 241-250页

作者： Paul Alexander JONES,Gillian Ruth MAY,Joyce Ann MCLUCKIE,Akinori IWASHITA,John SHARKEY Fujisawa Institute of neuroscience Division of neuroscience University of Edinburgh 1 George Square Edinburgh UK Medical Information Eli Lilly and Company ltd Lilly House Priestley Road Basingstoke RG24 9NL UK Fujisawa Institute of Neurosdence Division of neuroscience University of Edinburgh 1 George Square Edinburgh UK Medicinal Biology Research Laboratories Fujisawa Pharmaceuticals Co.ltd. 2-1-6 Kashima Yodogawa-ku Osaka 532-5814 Japan Fujisawa Institute of neuroscience Division of neuroscience University of Edinburgh 1 George Square Edinburgh UK

Characterising the mechanisms of cell death following focal cerebral ischaemia has been hampered by a lack of an in vitro assay emulating both the apoptotic and necrotic features observed in vivo. The present study systematically characterised oxygen-glucose-deprivation (OGD) in primary rat cortical neurones to establish a reproducible model with components of both cell-death endpoints. OGD induced a time-dependent reduction in cell viability, with 80% cell death occurring 24 h after 3 h exposure to 0% O2 and 0.5 mM glucose. Indicative of a necrotic component to OGD induced cell death, N-methyl-D-aspartate (NMDA) receptor inhibition with MK-801 attenuated neuronal loss by 60%. The lack of protection by the caspase inhibitors DEVD-CHO and z-VAD-fmk suggested that under these conditions neurones did not die by an apoptotic mechanism. Moderating the severity of the insult by decreasing OGD exposure to 60 min did not reduce the amount of necrosis, but did induce a small degree of apoptosis (a slight reductio

关键词： oxygen-glucose-deprivation caspase cortical necrosis.

Extension of the Lifespan of a Mouse Model of Rett Syndr.me by Intracerebroventricular Delivery of MECP2

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neuroscience Bulletin 2023年第2期39卷 297-302页

作者： Kan Yang Cheng Cheng Yiting Yuan Yuefang Zhang Shifang Shan Zilong Qiu Center for Excellence in Brain Science and Intelligence Technology Institute of NeuroscienceState Key Laboratory of NeuroscienceCAS Key Laboratory of Primate NeurobiologyChinese Academy of SciencesShanghai 200031China Belief BioMed(Shanghai) Co.Ltd.Shanghai 200032China National Clinical Research Center for Aging and Medicine Huashan HospitalFudan UniversityShanghai 200040China

DearEditors,Rett Syndr.me(RTT)is a severe neurodevelopmental disorder characterized by neural dysfunctions and a reduced lifespan,mainly in female patients,involving loss-of-function mutations in the methyl-CpG bindin... 详细信息

关键词： MECP2 Extension neural