Effect of GDNF gene transfer into axotomized retinal ganglion cells using in vivo electroporation with a contact lens-type electrode

Ishikawa, Hiroto; Takano, Masahiko; Matsumoto, Naoya; Sawada, Hajime; Idé, Chizuka; Mimura, Osamu; Dezawa, Mari

doi:10.1038/sj.gt.3302277

Cited by 60 publications

(34 citation statements)

References 40 publications

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“…This method has been successfully used previously to transfect RGCs. [36][37][38][39] Although ELP does not target RGCs specifically, and transfected cells were distributed not only in the GCL, but also in the inner nuclear layer; most of GCL transfected cells were colocalized with RGCs. We found that cells in the nasal superior or nasal inferior quadrants of the retina were transfected more efficiently than cells in other retinal regions.…”

Section: Discussionmentioning

confidence: 99%

“…51,52 ELP-mediated gene delivery was performed as described previously with minor modifications. 37,39 In brief, animals were anesthetized with an intramuscular injection of 0.8 ml kg À1 of a cocktail containing 5 ml ketamine (100 mg ml À1 ), 2.5 ml xylazine (20 mg ml À1 ), 1.0 ml acepromazine (10 mg ml À1 ), and 1.5 ml normal saline. Four microliters of plasmid DNA (20 mg) was injected into the vitreous cavity with a 34-gauge needle 0.5 mm posterior to the limbus under stereoscopic microscopy.…”

Section: Gene Transfer Into Rgcs With Electroporationmentioning

confidence: 99%

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Redox proteins thioredoxin 1 and thioredoxin 2 support retinal ganglion cell survival in experimental glaucoma

et al. 2008

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We investigated the neuroprotective effect of thioredoxin 1 (Trx1) and thioredoxin 2 (Trx2) which play critical roles in the regulation of oxidative stress on retinal ganglion cells (RGCs) in a rat glaucoma model. Expression of Trx1 and Trx2 and Trx-interacting protein (Txnip) was observed in the RGC layer (GCL), nerve fiber layer and inner nuclear layer. Txnip-, Trx1-and Trx2-expressing cells in the GCL were primarily colocalized with RGCs. The increased Txnip protein level was observed 2 and 5 weeks after glaucoma induction. Trx1 level decreased 2 weeks after glaucoma induction and more prominently after 5 weeks. No change in Trx2 levels was detected. The effects of Trx1 and Trx2 overexpression on RGC survival were evaluated 5 weeks after glaucoma induction. In nontransfected and EGFP-transfected (used as a negative control) retinas, RGC loss was approximately 27% compared with control. The loss of RGCs in Trx1-and Trx2-transfected retinas was approximately 15 and 17%, respectively. Thus, Trx1 and Trx2 preserved 45 and 37% of cells, respectively that were destined to die in glaucomatous retinas. The results of this study provide evidence for the involvement of oxidative stress in RGC degeneration in experimental glaucoma and point to potential strategies to reduce its impact.

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Section: Discussionmentioning

confidence: 99%

Section: Gene Transfer Into Rgcs With Electroporationmentioning

confidence: 99%

Redox proteins thioredoxin 1 and thioredoxin 2 support retinal ganglion cell survival in experimental glaucoma

et al. 2008

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“…73 GDNF gene transfer using an adenoviral vector or electroporation conferred protection of RGCs after optic nerve transaction. 44,74 Collectively, these studies highlight the potential of gene therapy to upregulate retinal neurotrophic factors that stimulate survival and/or regeneration of injured RGCs.…”

Section: Cracking the Case: Gene Therapy Strategies For Rgc Neuroprotmentioning

confidence: 99%

“…This approach has been used successfully to deliver neurotrophic factors and TXN thioredoxin genes to promote RGC survival in several models of optic nerve injury. [33][34][35] Small interference RNA (siRNA) has been successfully delivered to RGCs via injection into the superior colliculus; 36,37 however, the highly invasive nature of this approach limits its clinical application. Alternatively, siRNA can be injected intravitreally, leading to effective delivery to RGCs soon after administration (Figure 2).…”

Section: Tools For Gene Delivery To Injured Rgcsmentioning

confidence: 99%

Gene therapy for retinal ganglion cell neuroprotection in glaucoma

Wilson

Polo

2011

Gene Ther

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Glaucoma is the leading cause of irreversible blindness worldwide. The primary cause of glaucoma is not known, but several risk factors have been identified, including elevated intraocular pressure and age. Loss of vision in glaucoma is caused by the death of retinal ganglion cells (RGCs), the neurons that convey visual information from the retina to the brain. Therapeutic strategies aimed at delaying or halting RGC loss, known as neuroprotection, would be valuable to save vision in glaucoma. In this review, we discuss the significant progress that has been made in the use of gene therapy to understand mechanisms underlying RGC degeneration and to promote the survival of these neurons in experimental models of optic nerve injury. Gene Therapy (2012) 19, 127-136; doi:10.1038/gt.2011; published online 6 October 2011Keywords: retinal ganglion cell; neuroprotection; glaucoma NEUROPROTECTION IN GLAUCOMA: RATIONALE AND CURRENT LIMITATIONS Adult-onset glaucoma is an optic neuropathy that affects more than 50 million people around the world, with 47 million having bilateral (both eyes) blindness due to this disease. As more effective diagnostic tools become available, the number of cases is expected to rise, and a recent study predicts that there will be 70 million people with glaucoma in 2020. 1 Glaucoma is considered to be a group of diseases characterized by progressive optic nerve degeneration that results in visual field loss and irreversible blindness. The cause of glaucoma is unknown, but several risk factors have been identified, including high intraocular pressure, age and genetic predisposition. Open angle and angle-closure glaucoma, the most common forms of the disease, are often associated with high intraocular pressure. A crucial element in the pathophysiology of all forms of glaucoma is the death of retinal ganglion cells (RGCs; Figure 1) and, as these are central nervous system neurons, their loss is irreversible. At present, there is no cure for glaucoma, and the standard treatment is to lower intraocular pressure by medication or surgery. However, a significant proportion of patients continue to experience visual loss even when pharmacological treatments effectively reduce eye pressure. Therefore, novel therapeutic approaches are needed for its treatment and management.Early-onset glaucoma, comprising primary congenital glaucoma and juvenile open-angle glaucoma, has a clear genetic basis. Between 10 and 30% of individuals with juvenile open-angle glaucoma have mutations in the gene encoding myocilin, 2,3 and, on average, B40% of people with primary congenital glaucoma have mutations in the gene encoding cytochrome P450 protein. 4 Both genes are expressed in the trabecular meshwork and ciliary body, and defects in these genes may cause ocular hypertension. The elucidation of the genetic basis underlying adult-onset glaucoma is difficult because the late onset of disease limits the number of individuals available for linkage analysis. However, at least 29 genetic loci for various forms of glaucoma and 12...

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“…Using electrophoration, GDNF gene transferred into RGCs can increase RGC survival 2-4 weeks after ON transection. 39 Administration of adeno-associated virus (AAV) vector expressing CNTF into the eyes protects RGCs undergoing focal injury and local ischemia in rats. 40 AAV containing basic fibroblast growth factor (bFGF) or BDNF is neuroprotective to RGCs from excitatory injury caused by N-methyl-d-aspartic acid (NMDA) or nerve crush.…”

mentioning

confidence: 99%

Restoration of optic neuropathy

You¹,

Wu²,

Kuang³

et al. 2017

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Optic neuropathy refers to disorders involving the optic nerve (ON). Any damage to ON or ON-deriving neurons, the retinal ganglion cells (RGCs), may lead to the breakdown of the optical signal transmission from the eye to the brain, thus resulting in a partial or complete vision loss. The causes of optic neuropathy include trauma, ischemia, inflammation, compression, infiltration, and mitochondrial damages. ON injuries include primary and secondary injuries. During these injury phases, various factors orchestrate injured axons to die back and become unable to regenerate, and these factors could be divided into two categories: extrinsic and intrinsic. Extrinsic inhibitory factors refer to the environmental conditions that influence the regeneration of injured axons. The presence of myelin inhibitors and glial scar, lack of neurotrophic factors, and inflammation mediated by injury are regarded as these extrinsic factors. Extrinsic factors need to trigger the intracellular signals to exert inhibitory effect. Proper regulation of these intracellular signals has been shown to be beneficial to ON regeneration. Intrinsic factors of RGCs are the pivotal reasons that inhibit ON regeneration and are closely linked with extrinsic factors. Intracellular cyclic adenosine monophosphate (cAMP) and calcium levels affect axon guidance and growth cone response to guidance molecules. Many genes, such as Bcl-2, PTEN, and mTOR, are crucial in cell proliferation, axon guidance, and growth during development, and play important roles in the regeneration and extension of RGC axons. With transgenic mice and related gene regulations, robust regeneration of RGC axons has been observed after ON injury in laboratories. Although various means of experimental treatments such as cell transplantation and gene therapy have achieved significant progress in neuronal survival, axonal regeneration, and restoration of the visual function after ON injury, many unresolved scientific problems still exist for their clinical applications. Therefore, we still need to overcome hurdles before developing effective therapy to treat optic neuropathy diseases in patients.

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Effect of GDNF gene transfer into axotomized retinal ganglion cells using in vivo electroporation with a contact lens-type electrode

Cited by 60 publications

References 40 publications

Redox proteins thioredoxin 1 and thioredoxin 2 support retinal ganglion cell survival in experimental glaucoma

Redox proteins thioredoxin 1 and thioredoxin 2 support retinal ganglion cell survival in experimental glaucoma

Gene therapy for retinal ganglion cell neuroprotection in glaucoma

Restoration of optic neuropathy

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