Virus-mediated EpoR76E Therapy Slows Optic Nerve Axonopathy in Experimental Glaucoma

Bond, Wesley S.; Hines-Beard, Jessica; GoldenMerry, YPaul L.; Davis, Mara; Farooque, Alma; Sappington, Rebecca M.; Calkins, David J.; Rex, Tonia S.

doi:10.1038/mt.2015.198

Cited by 40 publications

(53 citation statements)

References 41 publications

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“…Consistent with previously published studies (Sappington et al, 2010; Lambert et al, 2011; Ward et al, 2014; Bond et al, 2016), microbead-induced IOP elevation in WT mice resulted in a 50% decrease in anterograde transport of CTB to the SC (Figure 3). Interestingly, IL-6 -/- mice exhibited a similar decrease in anterograde transport (Figure 3).…”

Section: Discussionsupporting

confidence: 91%

Interleukin-6 Deficiency Attenuates Retinal Ganglion Cell Axonopathy and Glaucoma-Related Vision Loss

2017

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The pleotropic cytokine interleukin-6 (IL-6) is implicated in retinal ganglion cell (RGC) survival and degeneration, including that associated with glaucoma. IL-6 protects RGCs from pressure-induced apoptosis in vitro. However, it is unknown how IL-6 impacts glaucomatous degeneration in vivo. To study how IL-6 influences glaucomatous RGC axonopathy, accompanying glial reactivity, and resultant deficits in visual function, we performed neural tracing, histological, and neurobehavioral assessments in wildtype (B6;129SF2/J; WT) and IL-6 knock-out mice (B6;129S2-IL6tm1kopf/J; IL-6-/-) after 8 weeks of unilateral or bilateral microbead-induced glaucoma (microbead occlusion model). IOP increased by 20% following microbead injection in both genotypes (p < 0.05). However, deficits in wound healing at the site of corneal injection were noted. In WT mice, elevated IOP produced degenerating axon profiles and decreased axon density in the optic nerve by 15% (p < 0.01). In IL-6-/- mice, axon density in the optic nerve did not differ between microbead- and saline-injected mice (p > 0.05) and degenerating axon profiles were minimal. Preservation of RGC axons was reflected in visual function, where visual acuity decreased significantly in a time-dependent manner with microbead-induced IOP elevation in WT (p < 0.001), but not IL-6-/- mice (p > 0.05). Despite this preservation of RGC axons and visual acuity, both microbead-injected WT and IL-6-/- mice exhibited a 50% decrease in anterograde CTB transport to the superior colliculus, as compared to saline-injected controls (p < 0.01). Assessment of glial reactivity revealed no genotype- or IOP-dependent changes in retinal astrocytes. IOP elevation decreased microglia density and percent retinal area covered in WT mice (p < 0.05), while IL-6-/- mice exhibited only a decrease in density (p < 0.05). Together, our findings indicate that two defining features of RGC axonopathy—axon transport deficits and structural degeneration of axons—likely occur via independent mechanisms. Our data suggest that IL-6 is part of a mechanism that specifically leads to structural degeneration of axons. Furthermore, its absence is sufficient to prevent both structural degeneration of the optic nerve and vision loss. Overall, our work supports the proposition that functional deficits in axon transport represent a therapeutic window for RGC axonopathy and identify IL-6 signaling as a strong target for such a therapeutic.

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Section: Discussionsupporting

confidence: 91%

Interleukin-6 Deficiency Attenuates Retinal Ganglion Cell Axonopathy and Glaucoma-Related Vision Loss

2017

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“…To allow local expression of targeted inhibitors of C3 activation to the retina of DBA/2J mice, we adopted ocular gene therapy using high-efficiency triple Y-F mutant capsid AAV2 vectors, which result in widespread and stable transduction of RGCs and inner retina in adult mice 47 . We performed bilateral, intravitreal injections of AAV2.GFP reporter at 10 10 total vector genomes per eye in 7 month-old DBA/2J mice, and confirmed efficient transduction of the inner retina in 10 month-old mice, consistent with previous reports of DBA/2J viral gene therapy [48][49][50][51] . Retinal wholemounts and radial sections showed GFP expression in the nerve fiber layer (NFL) and ganglion cell layer (GCL) (Figure 1A, B).…”

Section: Intravitreal Aav2cr2-crry Limits the Deposition Of C3d On Rgcssupporting

confidence: 87%

“…Ocular gene therapy viral vectors, such as adeno-associated virus (AAV), have been used to provide the diseased retina with local and permanent expression of Crry and other inhibitors, to chronically attenuate complement activation in models of age related macular degeneration [44][45][46] . Serotype 2 AAV vectors yield widespread transduction of the inner retina and RGCs 1 month after intravitreal injection in the mouse eye 47 , and over 10 months in the DBA/2J retina [48][49][50][51] . Thus, stable expression of targeted complement inhibitors via AAV gene therapy should be a viable approach to chronically attenuate complement activation during DBA/2J glaucoma progression.…”

Section: Introductionmentioning

confidence: 99%

Complement C3-targeted gene therapy restricts onset and progression of neurodegeneration in chronic mouse glaucoma

Bosco

Anderson

Breen

et al. 2018

Preprint

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Dysregulation of the complement system is implicated in neurodegeneration, including human and animal glaucoma. Optic nerve and retinal damage in glaucoma is preceded by local complement upregulation and activation, but whether targeting this early innate immune response could have therapeutic benefit remains undefined. Because complement signals through three pathways that intersect at complement C3 activation, here we targeted this step to restore complement balance in the glaucomatous retina, and to determine its contribution to degeneration onset and/or progression. To achieve this, we combined adeno-associated viral retinal gene therapy with the targeted C3 inhibitor CR2-Crry. We show that intravitreal injection of AAV2.CR2-Crry produced sustained Crry overexpression in the retina, and reduced deposition of the activation product complement C3d on retinal ganglion cells and the inner retina of DBA/2J mice.This resulted in neuroprotection of retinal ganglion cell axons and somata despite continued intraocular pressure elevation, suggesting a direct restriction of neurodegeneration onset and progression, and significant delay to terminal disease stages. Our study uncovers a damaging effect of complement C3 or downstream complement activation in glaucoma and establishes AAV2.CR2-Crry as a viable therapeutic strategy to target pathogenic C3-mediated complement activation in the glaucomatous retina.

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“…A recent report by Sullivan et al, demonstrated that AAV-mediated delivery of erythropoietin (AAV.EPOR76E) protected RGCs and axons in the D2 model of glaucoma (83). However, an additional study was performed to determine if the AAV.EPOR76E could also protect RGC axons in the mouse microbead occlusion model of elevated IOP and while the AAV.EPOR76E treated group appeared to have fewer degenerating axons when compared to the untreated group, there was no significant difference in the total number of axons between groups (84). …”

Section: Discussionmentioning

confidence: 99%

Overexpression of Soluble Fas Ligand following Adeno-Associated Virus Gene Therapy Prevents Retinal Ganglion Cell Death in Chronic and Acute Murine Models of Glaucoma

Krishnan

Fei

Jones

et al. 2016

The Journal of Immunology

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Glaucoma is a multifactorial disease resulting in the death of retinal ganglion cells (RGCs) and irreversible blindness. Glaucoma-associated RGC cell death depends on the pro-apoptotic and proinflammatory activity of membrane-bound FasL (mFasL). In contrast to mFasL, the natural soluble FasL cleavage product (sFasL) inhibits mFasL-mediated apoptosis and inflammation and is therefore a mFasL antagonist. DBA/2J (D2) mice spontaneously develop glaucoma and predictably RGC destruction is exacerbated by expression of a mutated membrane-only FasL (mFasL) gene that lacks the extracellular cleavage site. Remarkably, one time intraocular adeno-associated virus-mediated gene delivery of sFasL (AAV2.sFasL) provides complete and sustained neuroprotection in both the chronic D2 and acute microbead-induced models of glaucoma, even in the presence of elevated intraocular pressure (IOP). This protection correlated with inhibition of glial activation, reduced production of TNFα, and decreased apoptosis of RGCs and loss of axons. These data indicate that cleavage of FasL under homeostatic conditions, and the ensuing release of sFasL, normally limits the neurodestructive activity of FasL. The data further support the notion that sFasL, and not mFasL, contributes to the immune privileged status of the eye.

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Virus-mediated EpoR76E Therapy Slows Optic Nerve Axonopathy in Experimental Glaucoma

Cited by 40 publications

References 41 publications

Interleukin-6 Deficiency Attenuates Retinal Ganglion Cell Axonopathy and Glaucoma-Related Vision Loss

Interleukin-6 Deficiency Attenuates Retinal Ganglion Cell Axonopathy and Glaucoma-Related Vision Loss

Complement C3-targeted gene therapy restricts onset and progression of neurodegeneration in chronic mouse glaucoma

Overexpression of Soluble Fas Ligand following Adeno-Associated Virus Gene Therapy Prevents Retinal Ganglion Cell Death in Chronic and Acute Murine Models of Glaucoma

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