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

Abstract

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.

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Fig. 1: GFP and HA-tagged XIAP are expressed in retinas following intravitreal injections.
Fig. 2: Glaucoma surgeries successfully elevate and sustain pressure for at least 4 weeks.
Fig. 3: XIAP protects against RGC dysfunction in glaucoma.
Fig. 4: RGCs in XIAP-treated glaucoma eyes show reduced apoptosis and degeneration in comparison to GFP-treated eyes.
Fig. 5: XIAP-treated optic nerves show less axon loss and glial cell infiltration than GFP-treated optic nerves.
Fig. 6: Transmission electron microscopy (TEM) reveals healthier optic nerve morphology in XIAP-treated eyes.

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Acknowledgements

We wish to thank Jeff McClintock in the Electron Microscopy Lab at the Children’s Hospital of Eastern Ontario for technical help with electron microscopy and with optic nerve cross-sections, and Yves de Repentigny for help with protocols. We also thank members of the Laboratory of Adriana Di Polo, and especially Jorge Luis Cueva Vargas (Université de Montréal) for help in developing the microbead model.

Funding

This work was supported by a Glaucoma Research Society of Canada grants to CT. CT is supported by the Don and Joy Maclaren Endowed Chair in Vision Research. AAV vector production was partially supported by Research to Prevent Blindness at the University of Florida.

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SV was involved in data acquisition, data analysis, and writing of the manuscript. ANB was involved in data acquisition and generation of final figures. PSL was involved in data analysis and generation of figures. SGC was involved in research design and data analysis. GM was involved in research concept and design and protocol development. WWH generated the viruses for the study. CT obtained financial support for the study, and was involved in developing the research concept, design and protocols, and in writing the manuscript. All authors were involved in editing the manuscript.

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Correspondence to Catherine Tsilfidis.

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WWH owns shares in the company AGTC and is a paid consultant for them. No other competing financial interests exist.

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Visuvanathan, S., Baker, A.N., Lagali, P.S. et al. XIAP gene therapy effects on retinal ganglion cell structure and function in a mouse model of glaucoma. Gene Ther (2021). https://doi.org/10.1038/s41434-021-00281-7

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