Adeno-Associated Virus-Mediated RNAi against Mutant Alleles Attenuates Abnormal Calvarial Phenotypes in an Apert Syndrome Mouse Model.
Adeno-Associated Virus-Mediated RNAi against Mutant Alleles Attenuates Abnormal Calvarial Phenotypes in an Apert Syndrome Mouse Model.
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腺相关病毒介导的针对突变等位基因的 RNAi 可减轻阿珀特综合征小鼠模型中的异常颅骨表型
DOI：
10.1016/j.omtn.2018.09.012
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发表时间：
2018-12-07
期刊：
影响因子：
--
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Luo F;Xie Y;Wang Z;Huang J;Tan Q;Sun X;Li F;Li C;Liu M;Zhang D;Xu M;Su N;Ni Z;Jiang W;Chang J;Chen H;Chen S;Xu X;Deng C;Wang Z;Du X;Chen L
Apert综合征（AS）是颅缝早闭症的最严重形式，由错义突变引起，包括成纤维细胞生长因子受体2（FGFR 2）的Pro253 Arg（P253 R），其导致FGF/FGFR 2信号传导活性增强。手术矫正畸形颅骨是AS的典型治疗方法。由于缝线的持续发育不良，矫正手术通常要执行多次，导致患者挑战和并发症增加。靶向突变型FGFR 2等位基因信号传导的生物治疗结合手术可能会带来更好的结果。我们筛选并发现了一种特异性靶向Fgfr 2-P253 R等位基因的小干扰RNA（siRNA），并揭示了它通过降低培养的原代颅骨细胞和Apert小鼠颅骨外植体（Fgfr 2 +/P253 R）中ERK 1/2和P38信号转导来抑制成骨细胞分化和基质矿化。此外，将携带针对突变体Fgfr 2的短发夹RNA（shRNA）的AAV 9（AAV 9-Fgfr 2-shRNA）递送至AS小鼠的颅骨。结果表明，AAV 9-Fgfr 2-shRNA减轻了AS小鼠冠状缝的过早闭合和颅骨体积的减少。我们的研究提供了一种新的实用生物学方法，该方法将与其他治疗方法（包括手术）相结合，帮助治疗AS患者，同时为其他遗传性骨骼疾病的生物学治疗提供实验线索。
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.
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DOI：
10.1126/science.1236921
发表时间：
2013-10-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Jiang J;Wakimoto H;Seidman JG;Seidman CE
通讯作者：
Seidman CE
影响因子：
16.8
作者：
Haley, B;Zamore, PD
通讯作者：
Zamore, PD
DOI：
10.1016/j.bbrc.2004.03.098
发表时间：
2004-05-07
影响因子：
3.1
作者：
Chen, Y;Luk, KDK;Kung, HF
通讯作者：
Kung, HF
影响因子：
14.8
作者：
通讯作者：
--
影响因子：
4.1
作者：
Chen, L;Li, D;Deng, CX
通讯作者：
Deng, CX