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Neuroprotective therapies in glaucoma: I. Neurotrophic factor delivery

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Glaucoma is a neurodegenerative eye disease that causes permanent blindness at the progressive stage and the number of people affected worldwide is expected to reach over 79 million by 2020. Currently, glaucoma management relies on pharmacological and invasive surgical treatments mainly by reducing the intraocular pressure (IOP), which is the most important risk factor for the progression of the visual field loss. Recent research suggests that neuroprotective or neuroregenerative approaches are necessary to prevent retinal ganglion cells (RGCs) loss and visual impairment over time. Neuroprotection is a new therapeutic strategy that attempts to keep RGCs alive and functional. New gene and cell therapeutics encoding neurotrophic factors (NTFs) are emerging for both neuroprotection and regenerative treatments for retinal diseases. This article briefly reviews the role of NTFs in glaucoma and the potential delivery systems. WIREs Nanomed Nanobiotechnol 2016, 8:240–254. doi: 10.1002/wnan.1361 This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Schematic presentation of neurotrophic factor (NTF) signaling pathways relevant to glaucoma. Fibroblast growth factor 2 (FGF2), neurotrophin‐3 (NT‐3), and brain‐derived neurotrophic factor (BDNF) are the most relevant NTFs to glaucoma and increasing the levels of these factors has a positive effect on retinal ganglion cell (RGC) survival. NTFs bind to two families of receptors. Ligand formation with the tropomyosin kinase (Trk) receptor with high affinity activates the downstream survival (green) pathways. Trk binding promotes cell survival via phospholipase C‐γ (PLC‐γ) and Ca2+ and protein kinase pathways, the activation of Ras which in turn activates the mitogen‐activated protein kinase (MAPK signaling cascade, or the phosphoinositol‐3 kinase (PI3K) and protein kinase B (AKT) pathways. Binding of NTFs to low affinity p75 receptors, on the other hand, activates downstream cell death signals through JNK/Jun pathways, which elevate the proapoptotic P53 and Bax proteins and promote cell death. Restoring NTFs levels, on the other hand, results in activation of prosurvival pathways.
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Schematic representation of neurotrophic factor (NTF) gene therapy of the retina to provide neuroprotection and regeneration in glaucoma. Delivery approaches of NTF genes by systemic (intravenous) or local injection routes (only intravitreal is depicted for clarity), via ocular implants or by topical application are shown on the left. Nanoparticles carrying the NTF genes need to overcome several barrier layers within the eye (center) depending on the pathway of penetration toward the retina. The nanoparticles administered by intravitreal injection (dark blue particles) must migrate through the vitreous, a viscous biogel containing proteoglycans, collages, and hyaluronan before reaching the retinal layers, whereas topically administered nanoparticles may penetrate through a cornea‐posterior chamber‐vitreous‐retina pathway (light blue particles) or a conjunctiva‐sclera‐choroid‐retina pathway (medium blue particles). The targeted cells for NTF gene therapy within the retina are healthy retinal ganglion cells (RGCs) (bright blue), astrocytes (green), Muller glia cells (gray), and retinal pigment epithelium (RPE) (dark blue). Transduction of the retinal target cells may be achieved by nonviral vectors carrying the NTF encoding genes in vivo using intravitreal, subretinal, or other periocular injections or more propitiously by noninvasive topical administration. Alternatively, RGCs, astrocytes, Muller cells, and RPE could be genetically modified ex vivo to produce suitable levels of NTFs and then delivered to the retina to support stressed RGCs.
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Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease

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