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Adeno-Associated Virus-Mediated RNAi against Mutant Alleles Attenuates Abnormal Calvarial Phenotypes in an Apert Syndrome Mouse Model
Luo,Fengtao1; Xie,Yangli1; Wang,Zuqiang1; Huang,Junlan1; Tan,Qiaoyan1; Sun,Xianding1; Li,Fangfang1; Li,Can1; Liu,Mi1; Zhang,Dali1; Xu,Meng1; Su,Nan1; Ni,Zhenhong1; Jiang,Wanling1; Chang,Jinhong1; Chen,Hangang1; Chen,Shuai1; Xu,Xiaoling2; Deng,Chuxia2; Wang,Zhugang3; Du,Xiaolan1,4; Chen,Lin1
2018-12-07
Source PublicationMolecular Therapy - Nucleic Acids
Volume13Pages:291-302
AbstractApert syndrome (AS), the most severe form of craniosynostosis, is caused by missense mutations including Pro253Arg(P253R) of fibroblast growth factor receptor 2 (FGFR2), which leads to enhanced FGF/FGFR2-signaling activity. Surgical correction of the deformed skull is the typical treatment for AS. Because of constant maldevelopment of sutures, the corrective surgery is often executed several times, resulting in increased patient challenge and complications. Biological therapies targeting the signaling of mutant FGFR2 allele, in combination with surgery, may bring better outcome. Here we screened and found a small interfering RNA (siRNA) specifically targeting the Fgfr2-P253R allele, and we revealed that it inhibited osteoblastic differentiation and matrix mineralization by reducing the signaling of ERK1/2 and P38 in cultured primary calvarial cells and calvarial explants from Apert mice (Fgfr2). Furthermore, AAV9 carrying short hairpin RNA (shRNA) (AAV9-Fgfr2-shRNA) against mutant Fgfr2 was delivered to the skulls of AS mice. Results demonstrate that AAV9-Fgfr2-shRNA attenuated the premature closure of coronal suture and the decreased calvarial bone volume of AS mice. Our study provides a novel practical biological approach, which will, in combination with other therapies, including surgeries, help treat patients with AS while providing experimental clues for the biological therapies of other genetic skeletal diseases.
Keywordadeno-associated virus Apert syndrome craniosynostosis Fgfr2 molecular therapy RNAi
DOI10.1016/j.omtn.2018.09.012
URLView the original
Language英语
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Cited Times [WOS]:3   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorChen,Lin
Affiliation1.Laboratory for the Rehabilitation of Traumatic Injuries,Center of Bone Metabolism and Repair,State Key Laboratory of Trauma,Burns and Combined Injury,Trauma Center,Research Institute of Surgery,Daping Hospital,Third Military Medical University,Chongqing,400042,China
2.Faculty of Health Sciences,University of Macau,Macau SAR,Macao
3.State Key Laboratory of Medical Genomics,Research Center for Experimental Medicine,Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai,200025,China
4.Laboratory for the Rehabilitation of Traumatic Injuries,Center of Bone Metabolism and Repair,State Key Laboratory of Trauma,Trauma Center,Research Institute of Surgery,Daping Hospital,Third Military Medical University,Chongqing,400042,China
Recommended Citation
GB/T 7714
Luo,Fengtao,Xie,Yangli,Wang,Zuqiang,et al. Adeno-Associated Virus-Mediated RNAi against Mutant Alleles Attenuates Abnormal Calvarial Phenotypes in an Apert Syndrome Mouse Model[J]. Molecular Therapy - Nucleic Acids,2018,13:291-302.
APA Luo,Fengtao.,Xie,Yangli.,Wang,Zuqiang.,Huang,Junlan.,Tan,Qiaoyan.,...&Chen,Lin.(2018).Adeno-Associated Virus-Mediated RNAi against Mutant Alleles Attenuates Abnormal Calvarial Phenotypes in an Apert Syndrome Mouse Model.Molecular Therapy - Nucleic Acids,13,291-302.
MLA Luo,Fengtao,et al."Adeno-Associated Virus-Mediated RNAi against Mutant Alleles Attenuates Abnormal Calvarial Phenotypes in an Apert Syndrome Mouse Model".Molecular Therapy - Nucleic Acids 13(2018):291-302.
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