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XIAP Protects Retinal Ganglion Cells in the Mutant ND4 Mouse Model of Leber Hereditary Optic Neuropathy

PURPOSE: Leber hereditary optic neuropathy (LHON) is a genetic form of vision loss that occurs primarily owing to mutations in the nicotinamide adenine dinucleotide dehydrogenase (ND) subunits that make up complex I of the electron transport chain. LHON mutations result in the apoptotic death of ret...

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Autores principales: Wassmer, Sarah J., De Repentigny, Yves, Sheppard, Derek, Lagali, Pamela S., Fang, Lijun, Coupland, Stuart G., Kothary, Rashmi, Guy, John, Hauswirth, William W., Tsilfidis, Catherine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Association for Research in Vision and Ophthalmology 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425697/
https://www.ncbi.nlm.nih.gov/pubmed/32735323
http://dx.doi.org/10.1167/iovs.61.8.49
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author Wassmer, Sarah J.
De Repentigny, Yves
Sheppard, Derek
Lagali, Pamela S.
Fang, Lijun
Coupland, Stuart G.
Kothary, Rashmi
Guy, John
Hauswirth, William W.
Tsilfidis, Catherine
author_facet Wassmer, Sarah J.
De Repentigny, Yves
Sheppard, Derek
Lagali, Pamela S.
Fang, Lijun
Coupland, Stuart G.
Kothary, Rashmi
Guy, John
Hauswirth, William W.
Tsilfidis, Catherine
author_sort Wassmer, Sarah J.
collection PubMed
description PURPOSE: Leber hereditary optic neuropathy (LHON) is a genetic form of vision loss that occurs primarily owing to mutations in the nicotinamide adenine dinucleotide dehydrogenase (ND) subunits that make up complex I of the electron transport chain. LHON mutations result in the apoptotic death of retinal ganglion cells. We tested the hypothesis that gene therapy with the X-linked inhibitor of apoptosis (XIAP) would prevent retinal ganglion cell apoptosis and reduce disease progression in a vector-induced mouse model of LHON that carries the ND4 mutation. METHODS: Adeno-associated virus (AAV) encoding full length hemagglutinin-tagged XIAP (AAV2.HA-XIAP) or green fluorescent protein (AAV2.GFP) was injected into the vitreous of DBA/1J mice. Two weeks later, the LHON phenotype was induced by AAV delivery of mutant ND4 (AAV2.mND4FLAG) to the vitreous. Retinal function was assessed by pattern electroretinography. Optic nerves were harvested at 4 months, and the effects of XIAP therapy on nerve fiber layer and optic nerve integrity were evaluated using immunohistochemistry, transmission electron microscopy and magnetic resonance imaging. RESULTS: During LHON disease progression, retinal ganglion cell axons are lost. Apoptotic cell bodies are seen in the nuclei of astrocytes or oligodendrocytes in the optic nerve, and there is thinning of the optic nerve and the nerve fiber layer of the retina. At 4 months after disease onset, XIAP gene therapy protects the nerve fiber layer and optic nerve architecture by preserving axon health. XIAP also decreases nuclear fragmentation in resident astrocytes or oligodendrocytes and decreases glial cell infiltration. CONCLUSIONS: XIAP therapy improves optic nerve health and delays disease progression in LHON.
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spelling pubmed-74256972020-08-26 XIAP Protects Retinal Ganglion Cells in the Mutant ND4 Mouse Model of Leber Hereditary Optic Neuropathy Wassmer, Sarah J. De Repentigny, Yves Sheppard, Derek Lagali, Pamela S. Fang, Lijun Coupland, Stuart G. Kothary, Rashmi Guy, John Hauswirth, William W. Tsilfidis, Catherine Invest Ophthalmol Vis Sci Eye Movements, Strabismus, Amblyopia, and Neuro-Ophthalmology PURPOSE: Leber hereditary optic neuropathy (LHON) is a genetic form of vision loss that occurs primarily owing to mutations in the nicotinamide adenine dinucleotide dehydrogenase (ND) subunits that make up complex I of the electron transport chain. LHON mutations result in the apoptotic death of retinal ganglion cells. We tested the hypothesis that gene therapy with the X-linked inhibitor of apoptosis (XIAP) would prevent retinal ganglion cell apoptosis and reduce disease progression in a vector-induced mouse model of LHON that carries the ND4 mutation. METHODS: Adeno-associated virus (AAV) encoding full length hemagglutinin-tagged XIAP (AAV2.HA-XIAP) or green fluorescent protein (AAV2.GFP) was injected into the vitreous of DBA/1J mice. Two weeks later, the LHON phenotype was induced by AAV delivery of mutant ND4 (AAV2.mND4FLAG) to the vitreous. Retinal function was assessed by pattern electroretinography. Optic nerves were harvested at 4 months, and the effects of XIAP therapy on nerve fiber layer and optic nerve integrity were evaluated using immunohistochemistry, transmission electron microscopy and magnetic resonance imaging. RESULTS: During LHON disease progression, retinal ganglion cell axons are lost. Apoptotic cell bodies are seen in the nuclei of astrocytes or oligodendrocytes in the optic nerve, and there is thinning of the optic nerve and the nerve fiber layer of the retina. At 4 months after disease onset, XIAP gene therapy protects the nerve fiber layer and optic nerve architecture by preserving axon health. XIAP also decreases nuclear fragmentation in resident astrocytes or oligodendrocytes and decreases glial cell infiltration. CONCLUSIONS: XIAP therapy improves optic nerve health and delays disease progression in LHON. The Association for Research in Vision and Ophthalmology 2020-07-31 /pmc/articles/PMC7425697/ /pubmed/32735323 http://dx.doi.org/10.1167/iovs.61.8.49 Text en Copyright 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
spellingShingle Eye Movements, Strabismus, Amblyopia, and Neuro-Ophthalmology
Wassmer, Sarah J.
De Repentigny, Yves
Sheppard, Derek
Lagali, Pamela S.
Fang, Lijun
Coupland, Stuart G.
Kothary, Rashmi
Guy, John
Hauswirth, William W.
Tsilfidis, Catherine
XIAP Protects Retinal Ganglion Cells in the Mutant ND4 Mouse Model of Leber Hereditary Optic Neuropathy
title XIAP Protects Retinal Ganglion Cells in the Mutant ND4 Mouse Model of Leber Hereditary Optic Neuropathy
title_full XIAP Protects Retinal Ganglion Cells in the Mutant ND4 Mouse Model of Leber Hereditary Optic Neuropathy
title_fullStr XIAP Protects Retinal Ganglion Cells in the Mutant ND4 Mouse Model of Leber Hereditary Optic Neuropathy
title_full_unstemmed XIAP Protects Retinal Ganglion Cells in the Mutant ND4 Mouse Model of Leber Hereditary Optic Neuropathy
title_short XIAP Protects Retinal Ganglion Cells in the Mutant ND4 Mouse Model of Leber Hereditary Optic Neuropathy
title_sort xiap protects retinal ganglion cells in the mutant nd4 mouse model of leber hereditary optic neuropathy
topic Eye Movements, Strabismus, Amblyopia, and Neuro-Ophthalmology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425697/
https://www.ncbi.nlm.nih.gov/pubmed/32735323
http://dx.doi.org/10.1167/iovs.61.8.49
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