XIAP gene therapy effects on retinal ganglion cell structure and function in a mouse model of glaucoma

被引:16
作者
Visuvanathan, Shagana [1 ]
Baker, Adam N. [2 ]
Lagali, Pamela S. [2 ]
Coupland, Stuart G. [3 ,4 ,5 ]
Miller, Garfield [4 ,5 ]
Hauswirth, William W. [6 ]
Tsilfidis, Catherine [2 ,3 ,5 ]
机构
[1] Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada
[2] Ottawa Hosp, Neurosci, Res Inst, Ottawa, ON, Canada
[3] Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON, Canada
[4] Ottawa Hosp, Regenerat Med, Res Inst, Ottawa, ON, Canada
[5] Univ Ottawa, Dept Ophthalmol, Ottawa, ON, Canada
[6] Univ Florida, Coll Med, Dept Ophthalmol, Gainesville, FL 32610 USA
关键词
X-LINKED INHIBITOR; VISUAL-EVOKED POTENTIALS; OPTIC-NERVE HEAD; NF-KAPPA-B; OCULAR HYPERTENSION; NEUROTROPHIC FACTOR; DEGENERATION; ACTIVATION; APOPTOSIS; DEATH;
D O I
10.1038/s41434-021-00281-7
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Glaucoma is a prevalent neurodegenerative disease that is characterized by progressive visual field loss. It is the leading cause of irreversible blindness in the world. The main risk factor for glaucoma is elevated intraocular pressure that results in the damage and death of retinal ganglion cells (RGCs) and their axons. The death of RGCs has been shown to be apoptotic. We tested the hypothesis that blocking the activation of apoptosis may be an effective strategy to prevent RGC death and preserve functional vision in glaucoma. In the magnetic microbead mouse model of induced ocular hypertension, inhibition of RGC apoptosis was targeted through viral-mediated ocular delivery of the X-linked inhibitor of apoptosis (XIAP) gene, a potent caspase inhibitor. Pattern electroretinograms revealed that XIAP therapy resulted in significant protection of both somal and axonal RGC function in glaucomatous eyes. Histology confirmed that the treated optic nerves showed preservation of axon counts and reduced glial cell infiltration. These results show that XIAP is able to provide both functional and structural protection of RGCs in the microbead model of glaucoma and provide important proof-of-principle for XIAP's efficacy as a neuroprotective treatment for glaucoma.
引用
收藏
页码:147 / 156
页数:10
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