Glaucoma, Stem Cells, and Gene Therapy: Where Are We Now?

Daliri, Karim; Ljubimov, Alexander V.; Hekmatimoghaddam, Seyedhossein

doi:10.15283/ijsc17029

Cited by 25 publications

(17 citation statements)

References 64 publications

(67 reference statements)

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“…Cell-based therapies are becoming an increasingly recognized strategy with the potential to treat retinal neurodegenerative disease [ 124 , 125 ]. Unfortunately, in their current experimental settings, complex and indirect administration techniques are involved, with real-time monitoring of their integration into the host and effects on cell death often not possible.…”

Section: Retinal Apoptosis Visualization With Annexin A5mentioning

confidence: 99%

Annexins in Glaucoma

Yap

Davis²,

Guo³

et al. 2018

IJMS

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Glaucoma is one of the leading causes of irreversible visual loss, which has been estimated to affect 3.5% of those over 40 years old and projected to affect a total of 112 million people by 2040. Such a dramatic increase in affected patients demonstrates the need for continual improvement in the way we diagnose and treat this condition. Annexin A5 is a 36 kDa protein that is ubiquitously expressed in humans and is studied as an indicator of apoptosis in several fields. This molecule has a high calcium-dependent affinity for phosphatidylserine, a cell membrane phospholipid externalized to the outer cell membrane in early apoptosis. The DARC (Detection of Apoptosing Retinal Cells) project uses fluorescently-labelled annexin A5 to assess glaucomatous degeneration, the inherent process of which is the apoptosis of retinal ganglion cells. Furthermore, this project has conducted investigation of the retinal apoptosis in the neurodegenerative conditions of the eye and brain. In this present study, we summarized the use of annexin A5 as a marker of apoptosis in the eye. We also relayed the progress of the DARC project, developing real-time imaging of retinal ganglion cell apoptosis in vivo from the experimental models of disease and identifying mechanisms underlying neurodegeneration and its treatments, which has been applied to the first human clinical trials. DARC has potential as a biomarker in neurodegeneration, especially in the research of novel treatments, and could be a useful tool for the diagnosis and monitoring of glaucoma.

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Section: Retinal Apoptosis Visualization With Annexin A5mentioning

confidence: 99%

Annexins in Glaucoma

Yap

Davis²,

Guo³

et al. 2018

IJMS

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“…An increased production and/or decreased outflow of aqueous humor results in the development of elevated intraocular pressure (IOP) which is considered the main reason for enhanced apoptosis of RGCs in glaucoma [2]. Since RGCs are neurons, their spontaneous regeneration is not feasible, and accordingly, alleviation of IOP and consequent reduction of RGC loss are currently the main approach in glaucoma prevention and therapy [3].…”

Section: Introductionmentioning

confidence: 99%

“…The main target of pharmaceutical and surgical strategies for glaucoma treatment is trabecular meshwork (TM), an outflow system located around the base of the cornea that enables drainage of the aqueous humor [3]. Nevertheless, traditional TM-directed therapies, which downregulate IOP, may only delay progression of glaucoma and are not able to repopulate and/or regenerate RGCs and, therefore, are ineffective in most of patients with advanced glaucoma [1,3]. Accordingly, several new therapeutic approaches have been investigated for recovering from blindness or for maintenance of remaining vision in glaucoma [4].…”

Section: Introductionmentioning

confidence: 99%

“…Accordingly, several new therapeutic approaches have been investigated for recovering from blindness or for maintenance of remaining vision in glaucoma [4]. Because of their functional properties, mesenchymal stem cells (MSCs) have been the most extensively explored as new therapeutic agents in the cell-based therapy of glaucoma [3][4][5]. MSCs produce neurotrophins which promote survival and regeneration of injured RGCs in glaucomatous eyes [6].…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic Potential of Mesenchymal Stem Cells and Their Secretome in the Treatment of Glaucoma

Harrell

Fellabaum

Arsenijević

et al. 2019

Stem Cells International

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Glaucoma represents a group of progressive optic neuropathies characterized by gradual loss of retinal ganglion cells (RGCs), the neurons that conduct visual information from the retina to the brain. Elevated intraocular pressure (IOP) is considered the main reason for enhanced apoptosis of RGCs in glaucoma. Currently used therapeutic agents are not able to repopulate and/or regenerate injured RGCs and, therefore, are ineffective in most patients with advanced glaucoma. Accordingly, several new therapeutic approaches, including stem cell-based therapy, have been explored for the glaucoma treatment. In this review article, we emphasized current knowledge regarding molecular and cellular mechanisms responsible for beneficial effects of mesenchymal stem cells (MSCs) and their secretome in the treatment of glaucoma. MSCs produce neurotrophins and in an exosome-dependent manner supply injured RGCs with growth factors enhancing their survival and regeneration. Additionally, MSCs are able to generate functional RGC-like cells and induce proliferation of retinal stem cells. By supporting integrity of trabecular meshwork, transplanted MSCs alleviate IOP resulting in reduced loss of RGCs. Moreover, MSCs are able to attenuate T cell-driven retinal inflammation providing protection to the injured retinal tissue. In summing up, due to their capacity for neuroprotection and immunomodulation, MSCs and their secretome could be explored in upcoming clinical studies as new therapeutic agents for glaucoma treatment.

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“…Finally, structural and functional benefits or adverse effects can be easily followed-up by imaging, electrophysiology and behavioral tests. Cell-based therapies have been largely explored over the past few decades, notably for retinopathies due to photoreceptor and/or RPE cell death ( Goureau et al, 2014 ; Jayakody et al, 2015 ; Zarbin, 2016 ; Aghaizu et al, 2017 ; Jones et al, 2017 ; Llonch et al, 2018 ), and more recently for RGC disorders ( Sluch and Zack, 2014 ; Chamling et al, 2016 ; Daliri et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Pluripotent Stem Cell-Based Approaches to Explore and Treat Optic Neuropathies

2018

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Sight is a major sense for human and visual impairment profoundly affects quality of life, especially retinal degenerative diseases which are the leading cause of irreversible blindness worldwide. As for other neurodegenerative disorders, almost all retinal dystrophies are characterized by the specific loss of one or two cell types, such as retinal ganglion cells, photoreceptor cells, or retinal pigmented epithelial cells. This feature is a critical point when dealing with cell replacement strategies considering that the preservation of other cell types and retinal circuitry is a prerequisite. Retinal ganglion cells are particularly vulnerable to degenerative process and glaucoma, the most common optic neuropathy, is a frequent retinal dystrophy. Cell replacement has been proposed as a potential approach to take on the challenge of visual restoration, but its application to optic neuropathies is particularly challenging. Many obstacles need to be overcome before any clinical application. Beyond their survival and differentiation, engrafted cells have to reconnect with both upstream synaptic retinal cell partners and specific targets in the brain. To date, reconnection of retinal ganglion cells with distal central targets appears unrealistic since central nervous system is refractory to regenerative processes. Significant progress on the understanding of molecular mechanisms that prevent central nervous system regeneration offer hope to overcome this obstacle in the future. At the same time, emergence of reprogramming of human somatic cells into pluripotent stem cells has facilitated both the generation of new source of cells with therapeutic potential and the development of innovative methods for the generation of transplantable cells. In this review, we discuss the feasibility of stem cell-based strategies applied to retinal ganglion cells and optic nerve impairment. We present the different strategies for the generation, characterization and the delivery of transplantable retinal ganglion cells derived from pluripotent stem cells. The relevance of pluripotent stem cell-derived retinal organoid and retinal ganglion cells for disease modeling or drug screening will be also introduced in the context of optic neuropathies.

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Glaucoma, Stem Cells, and Gene Therapy: Where Are We Now?

Cited by 25 publications

References 64 publications

Annexins in Glaucoma

Annexins in Glaucoma

Therapeutic Potential of Mesenchymal Stem Cells and Their Secretome in the Treatment of Glaucoma

Pluripotent Stem Cell-Based Approaches to Explore and Treat Optic Neuropathies

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