Neuroprotective Effects of Transcription Factor Brn3b in an Ocular Hypertension Rat Model of Glaucoma

Stankowska, Dorota; Minton, Alena Z.; Rutledge, Margaret A.; Mueller, Brett H.; Phatak, Nitasha R.; He, Shuning; Ying, Hai; Forster, Michael J.; Yorio, Thomas; Krishnamoorthy, Raghu R

doi:10.1167/iovs.14-15008

Cited by 28 publications

(25 citation statements)

References 62 publications

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“…Over the past decade gene therapy has been tested in animal models of glaucoma as a treatment for glaucoma, delivering: neurotrophins (58), anti-apoptotic genes (57), and transcription factors (76) to the retina. There is substantial evidence in both human and experimental glaucoma animal models that RGCs die by apoptosis, but the molecular mechanisms that trigger apoptosis are not well understood (40–42).…”

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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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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“…The apoptosis of RGCs is the main cause of optic nerve damage in glaucoma, and numerous factors are involved in this process [52,53] . In addition, miRNAs exist in the retina [54] , and miRNAs are expressed in the retina of eyes with advanced glaucomatous damage [55] .…”

Section: The Relationship Between Mirna and The Apoptosis Of Rgcs Caumentioning

confidence: 99%

Relationship between the Pathogenesis of Glaucoma and miRNA

Guo

Shen

et al. 2017

Ophthalmic Res

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Small RNA (microRNA or miRNA) is a kind of small noncoding single-stranded RNA that regulates complementary mRNA at the posttranscriptional level in eukaryotic organisms. As important regulatory factors, miRNAs play an important role in the occurrence and development of glaucoma and widely participate in regulating biological processes of glaucoma-related genes. This article reviews the connection between the aqueous humor, trabecular meshwork, the apoptosis of retinal ganglion cells, and miRNA.

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“…Using the same rat chronic elevated IOP model, another recent survival study 124 was conducted using transcription factor BRN3B, a POU domain transcription factor known to be involved in maintaining retinal neurons. 125 To increase specificity, the authors generated an AAV2 viral vector where mouse Brn3b’ cDNA was led by the human neuronal-specific synapsin promoter.…”

Section: Retinal Ganglion Cell Targeting To Protect Degenerationmentioning

confidence: 99%

“…116 To increase detection and enhance transduction, the Brn3b cDNA was fused to a DDK flag and followed by the WPRE posttranscriptional regulatory enhancer element at the 3’. 124 The AAV2.hsyn.Brn3b-DDK. WPRE.bGH and control AAV2.hsyn.eGFP.WPRE.bGH were intravitreally injected in adult rats 1 week after IOP elevation.…”

Section: Retinal Ganglion Cell Targeting To Protect Degenerationmentioning

confidence: 99%

“…At 3–4 weeks, visual function (optomotor response), RGC counts, and axon integrity were all significantly improved in the Brn3b vector-injected animals compared with those in the GFP-injected controls. 124 Finally, in mice, an AAV2 carrying the gene encoding the overall cell defense protein heat shock protein 70 (Hsp-70) was injected into the mouse vitreous chamber 2 weeks before optic nerve crush. Two weeks later, RGC survival was 100% in the treated versus the untreated eye (636 cells versus 300 cells/mm 2 ).…”

Section: Retinal Ganglion Cell Targeting To Protect Degenerationmentioning

confidence: 99%

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Post-Vitrectomy Endophthalmitis in Victoria, Australia

Borrás

2017

Asia Pac J Ophthalmol (Phila)

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Treatment of diseases with gene therapy is advancing rapidly. The use of gene therapy has expanded from the original concept of replacing the mutated gene causing the disease to the use of genes to control nonphysiological levels of expression or to modify pathways known to affect the disease. Genes offer numerous advantages over conventional drugs. They have longer duration of action and are more specific. Genes can be delivered to the target site by naked DNA, cells, nonviral, and viral vectors. The enormous progress of the past decade in molecular biology and delivery systems has provided ways for targeting genes to the intended cell/tissue and safe, long-term vectors. The eye is an ideal organ for gene therapy. It is easily accessible and it is an immune-privileged site. Currently, there are clinical trials for diseases affecting practically every tissue of the eye, including those to restore vision in patients with Leber congenital amaurosis. However, the number of eye trials compared with those for systemic diseases is quite low (1.8%). Nevertheless, judging by the vast amount of ongoing preclinical studies, it is expected that such number will increase considerably in the near future. One area of great need for eye gene therapy is glaucoma, where a long-term gene drug would eliminate daily applications and compliance issues. Here, we review the current state of gene therapy for glaucoma and the possibilities for treating the trabecular meshwork to lower intraocular pressure and the retinal ganglion cells to protect them from neurodegeneration.

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Neuroprotective Effects of Transcription Factor Brn3b in an Ocular Hypertension Rat Model of Glaucoma

Abstract: Adeno-associated virus-mediated Brn3b protein expression may be a suitable approach for promoting neuroprotection in animal models of glaucoma.

Cited by 28 publications

References 62 publications

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

Relationship between the Pathogenesis of Glaucoma and miRNA

Post-Vitrectomy Endophthalmitis in Victoria, Australia

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