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Generation of nonhuman primate retinitis pigmentosa model by in situ knockout of RHO in rhesus macaque retina 被引量:4
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作者 Shouzhen Li yingzhou hu +15 位作者 Yunqin Li Min hu Wenchao Wang Yuqian Ma Yuan Cai Min Wei Yichuan Yao Yun Wang Kai Dong Yonghao Gu huan Zhao Jin Bao Zilong Qiu Mei Zhanga Xintian hu Tian Xue 《Science Bulletin》 SCIE EI CSCD 2021年第4期374-385,M0004,共13页
Retinitis pigmentosa(RP)is a form of inherited retinal degenerative diseases that ultimately involves the macula,which is present in primates but not in the rodents.Therefore,creating nonhuman primate(NHP)models of RP... Retinitis pigmentosa(RP)is a form of inherited retinal degenerative diseases that ultimately involves the macula,which is present in primates but not in the rodents.Therefore,creating nonhuman primate(NHP)models of RP is of critical importance to study its mechanism of pathogenesis and to evaluate potential therapeutic options in the future.Here we applied adeno-associated virus(AAV)-delivered CRISPR/SaCas9 technology to knockout the RHO gene in the retinae of the adult rhesus macaque(Macaca mulatta)to investigate the hypothesis whether non-germline mutation of the RHO gene is sufficient to recapitulate RP.Through a series of studies,we were able to demonstrate successful somatic editing of the RHO gene and reduced RHO protein expression.More importantly,the mutant macaque retinae displayed clinical RP phenotypes,including photoreceptor degeneration,retinal thinning,abnormal rod subcellular structures,and reduced photoresponse.Therefore,we suggest somatic editing of the RHO gene is able to phenocopy RP,and the reduced time span in generating NHP mutant accelerates RP research and expands the utility of NHP model for human disease study. 展开更多
关键词 Nonhuman primate model Retinitis pigmentosa RHODOPSIN Disease model Gene editing SaCas9
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Co-editing PINK1 and DJ-1 Genes Via Adeno-Associated Virus-Delivered CRISPR/Cas9 System in Adult Monkey Brain Elicits Classical Parkinsonian Phenotype 被引量:7
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作者 Hao Li Shihao Wu +13 位作者 Xia Ma Xiao Li Tianlin Cheng Zhifang Chen Jing Wu Longbao Lv Ling Li Liqi Xu Wenchao Wang yingzhou hu Haisong Jiang Yong Yin Zilong Qiu Xintian hu 《Neuroscience Bulletin》 SCIE CAS CSCD 2021年第9期1271-1288,共18页
Whether direct manipulation of Parkinson’s disease(PD)risk genes in the adult monkey brain can elicit a Parkinsonian phenotype remains an unsolved issue.Here,we used an adeno-associated virus serotype 9(AAV9)-deliver... Whether direct manipulation of Parkinson’s disease(PD)risk genes in the adult monkey brain can elicit a Parkinsonian phenotype remains an unsolved issue.Here,we used an adeno-associated virus serotype 9(AAV9)-delivered CRISPR/Cas9 system to directly co-edit PINK1 and DJ-1 genes in the substantia nigras(SNs)of two monkey groups:an old group and a middle-aged group.After the operation,the old group exhibited all the classic PD symptoms,including bradykinesia,tremor,and postural instability,accompanied by key pathological hallmarks of PD,such as severe nigral dopaminergic neuron loss(>64%)and evidentα-synuclein pathology in the gene-edited SN.In contrast,the phenotype of their middle-aged counterparts,which also showed clear PD symptoms and pathological hallmarks,were less severe.In addition to the higher final total PD scores and more severe pathological changes,the old group were also more susceptible to gene editing by showing a faster process of PD progression.These results suggested that both genetic and aging factors played important roles in the development of PD in the monkeys.Taken together,this system can effectively develop a large number of genetically-edited PD monkeys in a short time(6–10 months),and thus provides a practical transgenic monkey model for future PD studies. 展开更多
关键词 Parkinson’s disease MONKEY Adeno-associated virus-delivered CRISPR/Cas9 PINK1 DJ-1 Parkinsonian phenotype
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