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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90:262–7.
Downs JC, Roberts MD, Burgoyne CF. Mechanical environment of the optic nerve head in glaucoma. Optom Vis Sci. 2008;85:425–35.
Izzotti A, Bagnis A, Sacca SC. The role of oxidative stress in glaucoma. Mutat Res. 2006;612:105–14.
Hernandez MR. The optic nerve head in glaucoma: role of astrocytes in tissue remodeling. Prog Retin Eye Res. 2000;19:297–321.
Zeng HL, Shi JM. The role of microglia in the progression of glaucomatous neurodegeneration- a review. Int J Ophthalmol. 2018;11:143–9.
Johnson EC, Guo Y, Cepurna WO, Morrison JC. Neurotrophin roles in retinal ganglion cell survival: lessons from rat glaucoma models. Exp Eye Res. 2009;88:808–15.
Kerrigan LA, Zack DJ, Quigley HA, Smith SD, Pease ME. TUNEL-positive ganglion cells in human primary open-angle glaucoma. Arch Ophthalmol. 1997;115:1031–5.
Garcia-Valenzuela E, Shareef S, Walsh J, Sharma SC. Programmed cell death of retinal ganglion cells during experimental glaucoma. Exp Eye Res. 1995;61:33–44.
Quigley HA, Nickells RW, Kerrigan LA, Pease ME, Thibault DJ, Zack DJ. Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci. 1995;36:774–86.
Guo L, Moss SE, Alexander RA, Ali RR, Fitzke FW, Cordeiro MF. Retinal ganglion cell apoptosis in glaucoma is related to intraocular pressure and IOP-induced effects on extracellular matrix. Invest Ophthalmol Vis Sci. 2005;46:175–82.
McKinnon SJ, Lehman DM, Kerrigan-Baumrind LA, Merges CA, Pease ME, Kerrigan DF, et al. Caspase activation and amyloid precursor protein cleavage in rat ocular hypertension. Invest Ophthalmol Vis Sci. 2002;43:1077–87.
Huang W, Dobberfuhl A, Filippopoulos T, Ingelsson M, Fileta JB, Poulin NR, et al. Transcriptional up-regulation and activation of initiating caspases in experimental glaucoma. Am J Pathol. 2005;167:673–81.
Holcik M, Korneluk RG. XIAP, the guardian angel. Nat Rev Mol Cell Biol. 2001;2:550–6.
McKinnon SJ, Lehman DM, Tahzib NG, Ransom NL, Reitsamer HA, Liston P, et al. Baculoviral IAP repeat-containing-4 protects optic nerve axons in a rat glaucoma model. Mol Ther. 2002;5:780–7.
Renwick J, Narang MA, Coupland SG, Xuan JY, Baker AN, Brousseau J, et al. XIAP-mediated neuroprotection in retinal ischemia. Gene Ther. 2006;13:339–47.
Leonard KC, Petrin D, Coupland SG, Baker AN, Leonard BC, Lacasse EC, et al. XIAP protection of photoreceptors in animal models of retinitis pigmentosa. PLoS One. 2007;2:e314.
Petrin D, Baker A, Brousseau J, Coupland S, Liston P, Hauswirth WW, et al. XIAP protects photoreceptors from N-methyl-N-nitrosourea-induced retinal degeneration. In: LaVail MM, Hollyfield JG, Anderson RE, editors. Retinal degenerations: mechanisms and experimental therapy. 533. New York: Kluwer Academic/Plenum Publishers; 2003. p. 385–93.
Petrin D, Baker A, Coupland SG, Liston P, Narang M, Damji K, et al. Structural and functional protection of photoreceptors from MNU-induced retinal degeneration by the X-linked inhibitor of apoptosis. Invest Ophthalmol Vis Sci. 2003;44:2757–63.
Zadro-Lamoureux LA, Zacks DN, Baker AN, Zheng QD, Hauswirth WW, Tsilfidis C. XIAP effects on retinal detachment-induced photoreceptor apoptosis [corrected]. Invest Ophthalmol Vis Sci. 2009;50:1448–53.
Wassmer SJ, Leonard BC, Coupland SG, Baker AN, Hamilton J, Hauswirth WW, et al. Overexpression of the X-linked inhibitor of apoptosis protects against retinal degeneration in a feline model of retinal detachment. Hum Gene Ther. 2017;28:482–92.
Wassmer SJ, De Repentigny Y, Sheppard D, Lagali PS, Fang L, Coupland SG, et al. XIAP protects retinal ganglion cells in the mutant ND4 mouse model of leber hereditary optic neuropathy. Invest Ophthalmol Vis Sci. 2020;61:49.
Morrison JC, Cepurna WO, Johnson EC. Modeling glaucoma in rats by sclerosing aqueous outflow pathways to elevate intraocular pressure. Exp Eye Res. 2015;141:23–32.
Ito YA, Belforte N, Cueva Vargas JL, Di Polo A. A magnetic microbead occlusion model to induce ocular hypertension-dependent glaucoma in mice. J Vis Exp. 2016;109:e53731.
Hauswirth WW, Lewin AS, Zolotukhin S, Muzyczka N. Production and purification of recombinant adeno-associated virus. Methods Enzymol. 2000;316:743–61.
Zolotukhin S, Potter M, Zolotukhin I, Sakai Y, Loiler S, Fraites TJ Jr., et al. Production and purification of serotype 1, 2, and 5 recombinant adeno-associated viral vectors. Methods. 2002;28:158–67.
Shiozaki EN, Chai J, Rigotti DJ, Riedl SJ, Li P, Srinivasula SM, et al. Mechanism of XIAP-mediated inhibition of caspase-9. Mol Cell. 2003;11:519–27.
Scott FL, Denault JB, Riedl SJ, Shin H, Renatus M, Salvesen GS. XIAP inhibits caspase-3 and -7 using two binding sites: evolutionarily conserved mechanism of IAPs. EMBO J. 2005;24:645–55.
Chai J, Shiozaki E, Srinivasula SM, Wu Q, Dataa P, Alnemri ES, et al. Structural basis of caspase-7 inhibition by XIAP. Cell. 2001;104:769–80.
Deveraux QL, Takahashi R, Salvesen GS, Reed JC. X-linked IAP is a direct inhibitor of cell-death proteases. Nature. 1997;388:300–4.
Ding C, Wang P, Tian N. Effect of general anesthetics on IOP in elevated IOP mouse model. Exp Eye Res. 2011;92:512–20.
Quigley HA, Addicks EM, Green WR. Optic nerve damage in human glaucoma. III. Quantitative correlation of nerve fiber loss and visual field defect in glaucoma, ischemic neuropathy, papilledema, and toxic neuropathy. Arch Ophthalmol. 1982;100:135–46.
Tai TYT. Visual evoked potentials and glaucoma. Asia Pac J Ophthalmol (Phila). 2018;7:352–5.
Georgiou AL, Guo L, Francesca Cordeiro M, Salt TE. Electroretinogram and visual-evoked potential assessment of retinal and central visual function in a rat ocular hypertension model of glaucoma. Curr Eye Res. 2014;39:472–86.
Jha MK, Thakur D, Limbu N, Badhu BP, Paudel BH. Visual evoked potentials in primary open angle glaucoma. J Neurodegener Dis. 2017;2017:9540609.
Atkin A, Bodis-Wollner I, Podos SM, Wolkstein M, Mylin L, Nitzberg S. Flicker threshold and pattern VEP latency in ocular hypertension and glaucoma. Invest Ophthalmol Vis Sci. 1983;24:1524–8.
Parisi V. Neural conduction in the visual pathways in ocular hypertension and glaucoma. Graefes Arch Clin Exp Ophthalmol. 1997;235:136–42.
Parisi V, Miglior S, Manni G, Centofanti M, Bucci MG. Clinical ability of pattern electroretinograms and visual evoked potentials in detecting visual dysfunction in ocular hypertension and glaucoma. Ophthalmology. 2006;113:216–28.
Crish SD, Sappington RM, Inman DM, Horner PJ, Calkins DJ. Distal axonopathy with structural persistence in glaucomatous neurodegeneration. Proc Natl Acad Sci USA. 2010;107:5196–201.
Caleo M, Menna E, Chierzi S, Cenni MC, Maffei L. Brain-derived neurotrophic factor is an anterograde survival factor in the rat visual system. Curr Biol. 2000;10:1155–61.
Jakobs TC, Libby RT, Ben Y, John SW, Masland RH. Retinal ganglion cell degeneration is topological but not cell type specific in DBA/2J mice. J Cell Biol. 2005;171:313–25.
Buckingham BP, Inman DM, Lambert W, Oglesby E, Calkins DJ, Steele MR, et al. Progressive ganglion cell degeneration precedes neuronal loss in a mouse model of glaucoma. J Neurosci. 2008;28:2735–44.
Straten G, Schmeer C, Kretz A, Gerhardt E, Kugler S, Schulz JB, et al. Potential synergistic protection of retinal ganglion cells from axotomy-induced apoptosis by adenoviral administration of glial cell line-derived neurotrophic factor and X-chromosome-linked inhibitor of apoptosis. Neurobiol Dis. 2002;11:123–33.
Vince JE, Wong WW, Gentle I, Lawlor KE, Allam R, O’Reilly L, et al. Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation. Immunity. 2012;36:215–27.
Yabal M, Jost PJ. XIAP as a regulator of inflammatory cell death: the TNF and RIP3 angle. Mol Cell Oncol. 2015;2:e964622.
Yabal M, Muller N, Adler H, Knies N, Gross CJ, Damgaard RB, et al. XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation. Cell Rep. 2014;7:1796–808.
Hofer-Warbinek R, Schmid JA, Stehlik C, Binder BR, Lipp J, de Martin R. Activation of NF-kappa B by XIAP, the X chromosome-linked inhibitor of apoptosis, in endothelial cells involves TAK1. J Biol Chem. 2000;275:22064–8.
Kaur S, Wang F, Venkatraman M, Arsura M. X-linked inhibitor of apoptosis (XIAP) inhibits c-Jun N-terminal kinase 1 (JNK1) activation by transforming growth factor beta1 (TGF-beta1) through ubiquitin-mediated proteosomal degradation of the TGF-beta1-activated kinase 1 (TAK1). J Biol Chem. 2005;280:38599–608.
Lu M, Lin SC, Huang Y, Kang YJ, Rich R, Lo YC, et al. XIAP induces NF-kappaB activation via the BIR1/TAB1 interaction and BIR1 dimerization. Mol Cell. 2007;26:689–702.
Lawlor KE, Feltham R, Yabal M, Conos SA, Chen KW, Ziehe S, et al. XIAP loss triggers RIPK3- and caspase-8-driven IL-1beta activation and cell death as a consequence of TLR-MyD88-induced cIAP1-TRAF2 degradation. Cell Rep. 2017;20:668–82.
Lawlor KE, Khan N, Mildenhall A, Gerlic M, Croker BA, D’Cruz AA, et al. RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nat Commun. 2015;6:6282.
Liu W, Ha Y, Xia F, Zhu S, Li Y, Shi S, et al. Neuronal Epac1 mediates retinal neurodegeneration in mouse models of ocular hypertension. J Exp Med. 2020;217:e20190930.
Jang KH, Do YJ, Koo TS, Choi JS, Song EJ, Hwang Y, et al. Protective effect of RIPK1-inhibitory compound in in vivo models for retinal degenerative disease. Exp Eye Res. 2019;180:8–17.
Do YJ, Sul JW, Jang KH, Kang NS, Kim YH, Kim YG, et al. A novel RIPK1 inhibitor that prevents retinal degeneration in a rat glaucoma model. Exp Cell Res. 2017;359:30–8.
Kim BJ, Zack DJ. The role of c-Jun N-terminal kinase (JNK) in retinal degeneration and vision loss. Adv Exp Med Biol. 2018;1074:351–7.
Soto I, Howell GR. The complex role of neuroinflammation in glaucoma. Cold Spring Harb Perspect Med. 2014;4:a017269.
Williams PA, Marsh-Armstrong N, Howell GR. Lasker/IRRF Initiative on Astrocytes and Glaucomatous Neurodegeneration Participants Neuroinflammation in glaucoma: a new opportunity. Exp Eye Res. 2017;157:20–27.
Gherghel D, Orgul S, Gugleta K, Gekkieva M, Flammer J. Relationship between ocular perfusion pressure and retrobulbar blood flow in patients with glaucoma with progressive damage. Am J Ophthalmol. 2000;130:597–605.
Flammer J. [Glaucomatous optic neuropathy: a reperfusion injury]. Klin Monbl Augenheilkd. 2001;218:290–1.
Neufeld AH, Hernandez MR, Gonzalez M. Nitric oxide synthase in the human glaucomatous optic nerve head. Arch Ophthalmol. 1997;115:497–503.
Flammer J, Mozaffarieh M. What is the present pathogenetic concept of glaucomatous optic neuropathy? Surv Ophthalmol. 2007;52 Suppl 2:S162–73.
Evans MK, Sauer SJ, Nath S, Robinson TJ, Morse MA, Devi GR. X-linked inhibitor of apoptosis protein mediates tumor cell resistance to antibody-dependent cellular cytotoxicity. Cell Death Dis. 2016;7:e2073.
Levkovitch-Verbin H, Makarovsky D, Vander S. Comparison between axonal and retinal ganglion cell gene expression in various optic nerve injuries including glaucoma. Mol Vis. 2013;19:2526–41.
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.
Author information
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Competing interests
WWH owns shares in the company AGTC and is a paid consultant for them. No other competing financial interests exist.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
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 29, 147–156 (2022). https://doi.org/10.1038/s41434-021-00281-7
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41434-021-00281-7
This article is cited by
-
Inhibiting HIF-1 signaling alleviates HTRA1-induced RPE senescence in retinal degeneration
Cell Communication and Signaling (2023)
-
Apoptotic cell death in disease—Current understanding of the NCCD 2023
Cell Death & Differentiation (2023)