Effects of a combinatorial treatment with gene and cell therapy on retinal ganglion cell survival and axonal outgrowth after optic nerve injury

Nascimento-dos-Santos, Gabriel; Teixeira-Pinheiro, Leandro Coelho; Silva-Júnior, Almir Jordão da; Carvalho, Luiza; Mesentier-Louro, Louise A.; Hauswirth, William W.; Mendez-Otero, Rosália; Santiago, Marcelo F.; Petrs‐Silva, Hilda

doi:10.1038/s41434-019-0089-0

Cited by 15 publications

(16 citation statements)

References 67 publications

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“…A final reflection can be made on the possibility of using a multimodal therapy for diseases both of the retina and the optic nerve, which are complex and in which perhaps a single therapeutic approach would not work. In a recent paper [96], researchers from Brazil and Florida proposed an interesting combination of gene and cell therapy to increase RGC survival and their axon regrowth. This was an experimental study on a model of optic nerve crush, analyzing the neuroprotective and neuroregenerative potential of pigment epithelium-derived factor (PEDF) gene therapy alone and combined with human mesenchymal stem cell (hMSC) therapy.…”

Section: Ganglion Cell Replacement and Cell Therapy For Optic Nerve Diseases (Onds)mentioning

confidence: 99%

Cell Replacement Therapy for Retinal and Optic Nerve Diseases: Cell Sources, Clinical Trials and Challenges

2021

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The aim of this review was to provide an update on the potential of cell therapies to restore or replace damaged and/or lost cells in retinal degenerative and optic nerve diseases, describing the available cell sources and the challenges involved in such treatments when these techniques are applied in real clinical practice. Sources include human fetal retinal stem cells, allogenic cadaveric human cells, adult hippocampal neural stem cells, human CNS stem cells, ciliary pigmented epithelial cells, limbal stem cells, retinal progenitor cells (RPCs), human pluripotent stem cells (PSCs) (including both human embryonic stem cells (ESCs) and human induced pluripotent stem cells (iPSCs)) and mesenchymal stem cells (MSCs). Of these, RPCs, PSCs and MSCs have already entered early-stage clinical trials since they can all differentiate into RPE, photoreceptors or ganglion cells, and have demonstrated safety, while showing some indicators of efficacy. Stem/progenitor cell therapies for retinal diseases still have some drawbacks, such as the inhibition of proliferation and/or differentiation in vitro (with the exception of RPE) and the limited long-term survival and functioning of grafts in vivo. Some other issues remain to be solved concerning the clinical translation of cell-based therapy, including (1) the ability to enrich for specific retinal subtypes; (2) cell survival; (3) cell delivery, which may need to incorporate a scaffold to induce correct cell polarization, which increases the size of the retinotomy in surgery and, therefore, the chance of severe complications; (4) the need to induce a localized retinal detachment to perform the subretinal placement of the transplanted cell; (5) the evaluation of the risk of tumor formation caused by the undifferentiated stem cells and prolific progenitor cells. Despite these challenges, stem/progenitor cells represent the most promising strategy for retinal and optic nerve disease treatment in the near future, and therapeutics assisted by gene techniques, neuroprotective compounds and artificial devices can be applied to fulfil clinical needs.

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Section: Ganglion Cell Replacement and Cell Therapy For Optic Nerve Diseases (Onds)mentioning

confidence: 99%

Cell Replacement Therapy for Retinal and Optic Nerve Diseases: Cell Sources, Clinical Trials and Challenges

2021

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“…Cell-based delivery systems are also used to administer PEDF to the retina, by first infecting placental-derived [60], human mesenchymal-derived (hMSC) [59] and neural [58] stem cells with viral vectors, or transfecting primary rat RPE cells [62] in vitro with expression vectors, and generating in vitro PEDF-secreting cells that can be transplanted in the vitreous or in the subretinal space in vivo. The cell-based delivery systems of PEDF reported during the last five years are summarized in the Table 3.…”

Section: Genetic Administration Of Pedf and Cell-based Therapiesmentioning

confidence: 99%

“…The cell-based delivery systems of PEDF reported during the last five years are summarized in the Table 3. Most of these studies employ viral vectors to pack PEDF-coding DNA [58,59,61,63], and in vivo infections using mouse and rat models of retinal degeneration and neovascularization. Approaches using cell-based genetic administration of PEDF from mesenchymal stem cells, and subsequently implanting these PEDF-producing cells in the subretinal space or in the vitreous are emerging in studies aiming at the regeneration of the RPE layer.…”

Section: Genetic Administration Of Pedf and Cell-based Therapiesmentioning

confidence: 99%

Delivery Systems of Retinoprotective Proteins in the Retina

Rebustini¹,

Bernardo-Colón²,

Nalvarte³

et al. 2021

IJMS

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Retinoprotective proteins play important roles for retinal tissue integrity. They can directly affect the function and the survival of photoreceptors, and/or indirectly target the retinal pigment epithelium (RPE) and endothelial cells that support these tissues. Retinoprotective proteins are used in basic, translational and in clinical studies to prevent and treat human retinal degenerative disorders. In this review, we provide an overview of proteins that protect the retina and focus on pigment epithelium-derived factor (PEDF), and its effects on photoreceptors, RPE cells, and endothelial cells. We also discuss delivery systems such as pharmacologic and genetic administration of proteins to achieve photoreceptor survival and retinal tissue integrity.

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“…The combined treatment promoted the survival of significantly more injured RGCs than separate transplantations of each cell type [ 165 ]. Another study [ 166 ] combined intravitreal transplantations of WJ-MSCs with an AAV vector-mediated gene transfer of PEDF, a member of the serine proteinase inhibitor family that has been shown to promote RGC survival in vitro and in vivo [ 129 , 167 , 168 ]. The PEDF gene therapy promoted RGC survival in a rat ONC model for at least four weeks after the lesion, but—different to other reports—did not stimulate axon regeneration.…”

Section: Boosting Retinal Ganglion Cell Survival With Cell-based Combinatorial Neuroprotective Approachesmentioning

confidence: 99%

“…The pro-survival effect of PEDF coincided with increased levels of FGF-2, decreased levels of IL-1ß and attenuation of reactive microgliosis and astrogliosis when compared to eyes injected with a control vector. The combination of the gene therapy and the cell-based approach resulted in significantly higher numbers of viable RGCs and about twice as many regrowing axons in close vicinity to the lesion site than injections of MSCs only [ 166 ].…”

Section: Boosting Retinal Ganglion Cell Survival With Cell-based Combinatorial Neuroprotective Approachesmentioning

confidence: 99%

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

Grodzki

Bartsch

et al. 2021

Biology

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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.

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Effects of a combinatorial treatment with gene and cell therapy on retinal ganglion cell survival and axonal outgrowth after optic nerve injury

Cited by 15 publications

References 67 publications

Cell Replacement Therapy for Retinal and Optic Nerve Diseases: Cell Sources, Clinical Trials and Challenges

Cell Replacement Therapy for Retinal and Optic Nerve Diseases: Cell Sources, Clinical Trials and Challenges

Delivery Systems of Retinoprotective Proteins in the Retina

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

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