Adeno-Associated Virus-Mediated RNAi against Mutant Alleles Attenuates Abnormal Calvarial Phenotypes in an Apert Syndrome Mouse Model

Fengtao Luo; Yangli Xie; Zuqiang Wang; Junlan Huang; Qiaoyan Tan; Xianding Sun; Fangfang Li; Can Li; Mi Liu; Dali Zhang; Meng Xu; Nan Su; Zhenhong Ni; Wanling Jiang; Jinhong Chang; Hangang Chen; Shuai Chen; Xiaoling Xu; Chuxia Deng; Zhugang Wang; Xiaolan Du; Lin Chen

Molecular Therapy: Nucleic Acids (Dec 2018)

Adeno-Associated Virus-Mediated RNAi against Mutant Alleles Attenuates Abnormal Calvarial Phenotypes in an Apert Syndrome Mouse Model

Fengtao Luo,
Yangli Xie,
Zuqiang Wang,
Junlan Huang,
Qiaoyan Tan,
Xianding Sun,
Fangfang Li,
Can Li,
Mi Liu,
Dali Zhang,
Meng Xu,
Nan Su,
Zhenhong Ni,
Wanling Jiang,
Jinhong Chang,
Hangang Chen,
Shuai Chen,
Xiaoling Xu,
Chuxia Deng,
Zhugang Wang,
Xiaolan Du,
Lin Chen

Affiliations

Fengtao Luo: 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
Yangli Xie: 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
Zuqiang Wang: 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
Junlan Huang: 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
Qiaoyan Tan: 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
Xianding Sun: 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
Fangfang Li: 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
Can Li: 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
Mi Liu: 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
Dali Zhang: 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
Meng Xu: 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
Nan Su: 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
Zhenhong Ni: 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
Wanling Jiang: 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
Jinhong Chang: 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
Hangang Chen: 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
Shuai Chen: 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
Xiaoling Xu: Faculty of Health Sciences, University of Macau, Macau SAR, China
Chuxia Deng: Faculty of Health Sciences, University of Macau, Macau SAR, China
Zhugang Wang: 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
Xiaolan Du: 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; Corresponding author: Xiaolan Du, 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.
Lin Chen: 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; Corresponding author: Lin Chen, 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.

Journal volume & issue: Vol. 13
pp. 291 – 302

Abstract

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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+/P253R). 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. Keywords: craniosynostosis, Apert syndrome, Fgfr2, adeno-associated virus, RNAi, molecular therapy

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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