PTEN knockdown with the Y444F mutant AAV2 vector promotes axonal regeneration in the adult optic nerve

作     者：Zheng-ru Huang Hai-ying Chen Zi-zhong Hu Ping Xie Qing-huai Liu 

作者机构：Department of Ophthalmology the First Affiliated Hospital of Nanjing Medical University Nanjing Jiangsu Province China Department of Ophthalmology the Second People's Hospital of Changshu Changshu Jiangsu Province China 

出 版 物：《Neural Regeneration Research》 (中国神经再生研究（英文版）)

年 卷 期：2018年第13卷第1期

页      面：135-144页

核心收录：

学科分类：10[医学] 

基　　金：supported by the Research Foundation of Jiangsu Provincial Commission of Health and Family Planning of China,No.H201653 the Research Foundation of Changshu Science and Technology Bureau of China,No.CS201616 

主　　题：nerve regeneration optic nerve axotomy gene therapy Müller cell retinal ganglion cell AAV2 shRNA PTEN GLAST mTOR neural regeneration 

摘      要：The lack of axonal regeneration is the major cause of vision loss after optic nerve injury in adult mammals. Activating the PI3K/AKT/mTOR signaling pathway has been shown to enhance the intrinsic growth capacity of neurons and to facilitate axonal regeneration in the central nervous system after injury. The deletion of the mTOR negative regulator phosphatase and tensin homolog （PTEN） enhances regeneration of adult corticospinal neurons and ganglion cells. In the present study, we used a tyrosine-mutated （Y444F） AAV2 vector to efficiently express a short hairpin RNA （shRNA） for silencing PTEN expression in retinal ganglion cells. We evaluated cell survival and axonal regeneration in a rat model of optic nerve axotomy. The rats received an intravitreal injection of wildtype AAV2 or Y444F mutant AAV2 （both carrying shRNA to PTEN） 4 weeks before optic nerve axotomy. Compared with the wildtype AAV2 vector, the Y444F mutant AAV2 vector enhanced retinal ganglia cell survival and stimulated axonal regeneration to a greater extent 6 weeks after axotomy. Moreover,post-axotomy injection of the Y444F AAV2 vector expressing the shRNA to PTEN rescued ～19% of retinal ganglion cells and induced axons to regenerate near to the optic chiasm. Taken together, our results demonstrate that PTEN knockdown with the Y444F AAV2 vector promotes retinal ganglion cell survival and stimulates long-distance axonal regeneration after optic nerve axotomy. Therefore, the Y444F AAV2 vector might be a promising gene therapy tool for treating optic nerve injury.