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Adeno-Associated Virus-Mediated RNAi against Mutant Alleles Attenuates Abnormal Calvarial Phenotypes in an Apert Syndrome Mouse Model
Luo F.1; Xie Y.1; Wang Z.1; Huang J.1; Tan Q.1; Sun X.1; Li F.1; Li C.1; Liu M.1; Zhang D.1; Xu M.1; Su N.1; Ni Z.1; Jiang W.1; Chang J.1; Chen H.1; Chen S.1; Xu X.3; Deng C.3; Wang Z.2; Du X.1; Chen L.1
2018-12-07
Source PublicationMolecular Therapy - Nucleic Acids
ISSN21622531
Volume13Pages:291-302
Abstract

Apert 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
Indexed BySCI
Language英语
WOS Research AreaResearch & Experimental Medicine
WOS SubjectMedicine, Research & Experimental
WOS IDWOS:000452325300025
PublisherCELL PRESS
Fulltext Access
Citation statistics
Cited Times [WOS]:3   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Co-First AuthorLuo F.
Corresponding AuthorDu X.; Chen L.
Affiliation1.Daping Hospital, the Third Military Medical University
2.Shanghai Jiao Tong University School of Medicine
3.Universidade de Macau
Recommended Citation
GB/T 7714
Luo F.,Xie Y.,Wang Z.,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 F..,Xie Y..,Wang Z..,Huang J..,Tan Q..,...&Chen L..(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 F.,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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