A Hypoxia-Responsive Glial Cell-Specific Gene Therapy Vector for Targeting Retinal Neovascularization

Biswal, Manas R.; Hm, Prentice; Ck, Dorey; Blanks, Janet C.

doi:10.1167/iovs.14-13932

Cited by 34 publications

(22 citation statements)

References 64 publications

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“…Interestingly, reactive gliosis in retinal explants from db/db mice was also reduced by the treatment with DSO 2 -ONJ. As reactive gliosis is present in DR [7,58,59], our results might have therapeutic implications proposing a novel strategy for its treatment based on the specific induction of HO-1 in the retina.…”

Section: Discussionmentioning

confidence: 75%

The sp 2 -iminosugar glycolipid 1-dodecylsulfonyl-5 N ,6 O -oxomethylidenenojirimycin (DSO 2 -ONJ) as selective anti-inflammatory agent by modulation of hemeoxygenase-1 in Bv.2 microglial cells and retinal explants

Alcalde-Estévez

Arroba

Sánchez-Fernández

et al. 2018

Food and Chemical Toxicology

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Neuroinflammation is an early event during diabetic retinopathy (DR) that impacts the dynamics of microglia polarization. Gliosis is a hallmark of DR and we have reported the beneficial effects of 1R-DSO-ONJ, a member of the sp-iminosugar glycolipid (sp-IGL) family, in targeting microglia and reducing gliosis in diabetic db/db mice. Herein, we analyzed the effect of DSO-ONJ, another family compound incorporating a sulfone group that better mimics the phosphate group of phosphatidylinositol ether lipid analogues (PIAs), in Bv.2 microglial cells treated with bacterial lipopolysaccaride (LPS) and in retinal explants from db/db mice. In addition to decreasing iNOS and inflammasome activation, the anti-inflammatory effect of DSO-ONJ was mediated by direct p38α MAPK activation. Computational docking experiments demonstrated that DSO-ONJ binds to p38α MAPK at the same site where PIAs and the alkyl phospholipid perifosine activators do, suggesting similar mechanism of action. Moreover, treatment of microglial cells with DSO-ONJ increased both heme-oxygenase (HO)-1 and Il10 expression regardless the presence of LPS. In retinal explants from db/db mice, DSO-ONJ also induced HO-1 and reduced gliosis. Since IL-10-mediated induction of HO-1 expression is mediated by p38α MAPK activation, our results suggest that this molecular mechanism is involved in the anti-inflammatory effects of DSO-ONJ in microglia.

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Section: Discussionmentioning

confidence: 75%

The sp 2 -iminosugar glycolipid 1-dodecylsulfonyl-5 N ,6 O -oxomethylidenenojirimycin (DSO 2 -ONJ) as selective anti-inflammatory agent by modulation of hemeoxygenase-1 in Bv.2 microglial cells and retinal explants

Alcalde-Estévez

Arroba

Sánchez-Fernández

et al. 2018

Food and Chemical Toxicology

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“…However, successful in vivo application of such promoters in animal models of ocular disease and neurodegeneration is rare. A successful in vivo application of a hypoxia-inducible promoter for treatment of ischemic retinopathy models has been reported 45 . Similarly, the utility has been reported in the murine middle cerebral artery occlusion model 46 .…”

Section: Discussionmentioning

confidence: 84%

Spatially and Temporally Regulated NRF2 Gene Therapy Using Mcp-1 Promoter in Retinal Ganglion Cell Injury

Fujita

Nishiguchi

Shiga

et al. 2017

Molecular Therapy - Methods & Clinical Development

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Retinal ganglion cell degeneration triggered by axonal injury is believed to underlie many ocular diseases, including glaucoma and optic neuritis. In these diseases, retinal ganglion cells are affected unevenly, both spatially and temporally, such that healthy and unhealthy cells coexist in different patterns at different time points. Herein, we describe a temporally and spatially regulated adeno-associated virus gene therapy aiming to reduce undesired off-target effects on healthy retinal neurons. The Mcp-1 promoter previously shown to be activated in stressed retinal ganglion cells following murine optic nerve injury was combined with the neuroprotective intracellular transcription factor Nrf2. In this model, Mcp-1 promoter-driven NRF2 expression targeting only stressed retinal ganglion cells showed efficacy equivalent to non-selective cytomegalovirus promoter-driven therapy for preventing cell death. However, cytomegalovirus promoter-mediated NRF2 transcription induced cellular stress responses and death of Brn3A-positive uninjured retinal ganglion cells. Such undesired effects were reduced substantially by adopting the Mcp-1 promoter. Combining a stress-responsive promoter and intracellular therapeutic gene is a versatile approach for specifically targeting cells at risk of degeneration. This strategy may be applicable to numerous chronic ocular and non-ocular conditions.

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“…Retinal hypoxia caused by retinal vessel occlusion or capillary nonperfusion in retinopathies stimulates the production of angiogenic factors, leading to intraocular neovascularization (NV). [1][2][3] The predominant growth factor associated with physiological and pathophysiological angiogenesis is vascular endothelial growth factor a (VEGFa). Several ocular cell types are known to express VEGFa (e.g., Müller cells, pericytes, ganglion cells, and vascular endothelial cells [ECs]), which plays a critical role in retinal neovascularization.…”

mentioning

confidence: 99%

Sphingosine Kinase 2 Modulates Retinal Neovascularization in the Mouse Model of Oxygen-Induced Retinopathy

Eresch

Stumpf

Koch

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Neovascularization is a major cause of blindness in various ocular diseases. Bioactive sphingosine 1-phosphate (S1P), synthesized by two sphingosine kinases (Sphk1, Sphk2), emerged as a key player in a multitude of cellular processes, including cell survival, proliferation, inflammation, migration, and angiogenesis. We investigated the role of Sphk2, S1P, and S1P receptors (S1PR) during retinal neovascularization using the oxygen-induced retinopathy mouse model (OIR). METHODS. Sphk2 overexpressing (tgSphk2) and Sphk2 knockout (Sphk2) mice were used in the OIR model, exposed to 75% O 2 over 5 days from postnatal day (P)7 to 12 to initiate vessel regression. After returning to room air, these mice developed a marked neovascularization. Retinae recovered from untreated and treated eyes at P7, P12, P14, and P17 were used for lectin-stained retinal whole mounts, mass spectrometry, and quantitative real-time PCR.RESULTS. tgSphk2 mice showed higher retinal S1P concentrations, accelerated retinal angiogenesis, and increased neovascularization. Expression of S1PR, vascular endothelial growth factor a (VEGFa), and angiopoietin 1 and 2 was differentially regulated during the course of OIR in the different genotypes. Sphk2À/À displayed a markedly reduced retinal angiogenesis and neovascularization as well as decreased VEGFa and angiopoietin expression.CONCLUSIONS. Using genetic models of Sphk2 overexpression or deletion we demonstrate a strong impact of Sphk2/S1P on retinal vasculopathy and expression of vascular growth factors like VEGF and angiopoietin in the retina. Consequently, Sphk2, S1P, and S1PR may offer attractive novel therapeutic targets for ischemic retinopathies.

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A Hypoxia-Responsive Glial Cell-Specific Gene Therapy Vector for Targeting Retinal Neovascularization

Abstract: These findings suggest that the hypoxia-regulated, glial cell-specific vector expressing endostatin may be useful for treatment of neovascularization in proliferative diabetic retinopathy.

Cited by 34 publications

References 64 publications

The sp 2 -iminosugar glycolipid 1-dodecylsulfonyl-5 N ,6 O -oxomethylidenenojirimycin (DSO 2 -ONJ) as selective anti-inflammatory agent by modulation of hemeoxygenase-1 in Bv.2 microglial cells and retinal explants

The sp 2 -iminosugar glycolipid 1-dodecylsulfonyl-5 N ,6 O -oxomethylidenenojirimycin (DSO 2 -ONJ) as selective anti-inflammatory agent by modulation of hemeoxygenase-1 in Bv.2 microglial cells and retinal explants

Spatially and Temporally Regulated NRF2 Gene Therapy Using Mcp-1 Promoter in Retinal Ganglion Cell Injury

Sphingosine Kinase 2 Modulates Retinal Neovascularization in the Mouse Model of Oxygen-Induced Retinopathy

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