scholarly journals Target-Derived Neurotrophic Factor Deprivation Puts Retinal Ganglion Cells on Death Row: Cold Hard Evidence and Caveats

2019 ◽  
Vol 20 (17) ◽  
pp. 4314 ◽  
Author(s):  
Marie Claes ◽  
Lies De Groef ◽  
Lieve Moons
Keyword(s):  
Animal Models ◽  
Disease Progression ◽  
Retinal Ganglion Cells ◽  
Neurotrophic Factors ◽  
Neurotrophic Factor ◽  
Ganglion Cells ◽  
Retrograde Transport ◽  
Retinal Ganglion ◽  
Hard Evidence ◽  
Glaucoma Treatment

Glaucoma and other optic neuropathies are characterized by axonal transport deficits. Axonal cargo travels back and forth between the soma and the axon terminus, a mechanism ensuring homeostasis and the viability of a neuron. An example of vital molecules in the axonal cargo are neurotrophic factors (NTFs). Hindered retrograde transport can cause a scarcity of those factors in the retina, which in turn can tilt the fate of retinal ganglion cells (RGCs) towards apoptosis. This postulation is one of the most widely recognized theories to explain RGC death in the disease progression of glaucoma and is known as the NTF deprivation theory. For several decades, research has been focused on the use of NTFs as a novel neuroprotective glaucoma treatment. Until now, results in animal models have been promising, but translation to the clinic has been highly disappointing. Are we lacking important knowledge to lever NTF therapies towards the therapeutic armamentarium? Or did we get the wrong end of the stick regarding the NTF deprivation theory? In this review, we will tackle the existing evidence and caveats advocating for and against the target-derived NTF deprivation theory in glaucoma, whilst digging into associated therapy efforts.

scholarly journals Cell-Based Neuroprotection of Retinal Ganglion Cells in Animal Models of Optic Neuropathies

Biology ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1181
Author(s):  
Yue Hu ◽  
Lynn Michelle Grodzki ◽  
Susanne Bartsch ◽  
Udo Bartsch
Keyword(s):  
Animal Models ◽  
Ganglion Cell ◽  
Retinal Ganglion Cells ◽  
Neurotrophic Factors ◽  
Visual Information ◽  
Therapeutic Potential ◽  
Ganglion Cells ◽  
Treatment Strategies ◽  
Projection Neurons ◽  
Retinal Ganglion

Retinal ganglion cells (RGCs) comprise a heterogenous group of projection neurons that transmit visual information from the retina to the brain. Progressive degeneration of these cells, as it occurs in inflammatory, ischemic, traumatic or glaucomatous optic neuropathies, results in visual deterioration and is among the leading causes of irreversible blindness. Treatment options for these diseases are limited. Neuroprotective approaches aim to slow down and eventually halt the loss of ganglion cells in these disorders. In this review, we have summarized preclinical studies that have evaluated the efficacy of cell-based neuroprotective treatment strategies to rescue retinal ganglion cells from cell death. Intraocular transplantations of diverse genetically nonmodified cell types or cells engineered to overexpress neurotrophic factors have been demonstrated to result in significant attenuation of ganglion cell loss in animal models of different optic neuropathies. Cell-based combinatorial neuroprotective approaches represent a potential strategy to further increase the survival rates of retinal ganglion cells. However, data about the long-term impact of the different cell-based treatment strategies on retinal ganglion cell survival and detailed analyses of potential adverse effects of a sustained intraocular delivery of neurotrophic factors on retina structure and function are limited, making it difficult to assess their therapeutic potential.

scholarly journals A Safe GDNF and GDNF/BDNF Controlled Delivery System Improves Migration in Human Retinal Pigment Epithelial Cells and Survival in Retinal Ganglion Cells: Potential Usefulness in Degenerative Retinal Pathologies

2021 ◽  
Vol 14 (1) ◽  
pp. 50
Author(s):  
Alicia Arranz-Romera ◽  
Maria Hernandez ◽  
Patricia Checa-Casalengua ◽  
Alfredo Garcia-Layana ◽  
Irene T. Molina-Martinez ◽  
...  
Keyword(s):  
Cell Viability ◽  
Retinal Ganglion Cells ◽  
Neurotrophic Factor ◽  
Retinal Pigment Epithelial ◽  
Ganglion Cells ◽  
Retinal Pigment ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Retinal Ganglion ◽  
Pigment Epithelial

We assessed the sustained delivery effect of poly (lactic-co-glycolic) acid (PLGA)/vitamin E (VitE) microspheres (MSs) loaded with glial cell-derived neurotrophic factor (GDNF) alone (GDNF-MSs) or combined with brain-derived neurotrophic factor (BDNF; GDNF/BDNF-MSs) on migration of the human adult retinal pigment epithelial cell-line-19 (ARPE-19) cells, primate choroidal endothelial (RF/6A) cells, and the survival of isolated mouse retinal ganglion cells (RGCs). The morphology of the MSs, particle size, and encapsulation efficiencies of the active substances were evaluated. In vitro release, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability, terminal deoxynucleotidyl transferase (TdT) deoxyuridine dUTP nick-end labelling (TUNEL) apoptosis, functional wound healing migration (ARPE-19; migration), and (RF/6A; angiogenesis) assays were conducted. The safety of MS intravitreal injection was assessed using hematoxylin and eosin, neuronal nuclei (NeuN) immunolabeling, and TUNEL assays, and RGC in vitro survival was analyzed. MSs delivered GDNF and co-delivered GDNF/BDNF in a sustained manner over 77 days. The BDNF/GDNF combination increased RPE cell migration, whereas no effect was observed on RF/6A. MSs did not alter cell viability, apoptosis was absent in vitro, and RGCs survived in vitro for seven weeks. In mice, retinal toxicity and apoptosis was absent in histologic sections. This delivery strategy could be useful as a potential co-therapy in retinal degenerations and glaucoma, in line with future personalized long-term intravitreal treatment as different amounts (doses) of microparticles can be administered according to patients’ needs.

scholarly journals Midget retinal ganglion cell dendritic and mitochondrial degeneration is an early feature of human glaucoma

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
James R Tribble ◽  
Asta Vasalauskaite ◽  
Tony Redmond ◽  
Robert D Young ◽  
Shoaib Hassan ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Animal Models ◽  
Ganglion Cell ◽  
Retinal Ganglion Cells ◽  
Retinal Ganglion Cell ◽  
Ganglion Cells ◽  
Retinal Ganglion ◽  
Face Scanning ◽  
Block Face ◽  
Scanning Electron

Abstract Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells. However, the earliest degenerative events that occur in human glaucoma are relatively unknown. Work in animal models has demonstrated that retinal ganglion cell dendrites remodel and atrophy prior to the loss of the cell soma. Whether this occurs in human glaucoma has yet to be elucidated. Serial block face scanning electron microscopy is well established as a method to determine neuronal connectivity at high resolution but so far has only been performed in normal retina from animal models. To assess the structure–function relationship of early human glaucomatous neurodegeneration, regions of inner retina assessed to have none-to-moderate loss of retinal ganglion cell number were processed using serial block face scanning electron microscopy (n = 4 normal retinas, n = 4 glaucoma retinas). This allowed detailed 3D reconstruction of retinal ganglion cells and their intracellular components at a nanometre scale. In our datasets, retinal ganglion cell dendrites degenerate early in human glaucoma, with remodelling and redistribution of the mitochondria. We assessed the relationship between visual sensitivity and retinal ganglion cell density and discovered that this only partially conformed to predicted models of structure–function relationships, which may be affected by these early neurodegenerative changes. In this study, human glaucomatous retinal ganglion cells demonstrate compartmentalized degenerative changes as observed in animal models. Importantly, in these models, many of these changes have been demonstrated to be reversible, increasing the likelihood of translation to viable therapies for human glaucoma.

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