Recent Progress in Retinal Pigment Epithelium Cell-Based Therapy for Retinal Disease

Klymenko, Valeriia; González Martínez, Orlando G; Zarbin, Marco

doi:10.1093/stcltm/szae004

Cited by 3 publications

(1 citation statement)

References 82 publications

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“…Although, PROM1 has been previously knocked out in RPE cells [ 30 , 78 ] and murine models [ 79 – 81 ], the application of CRISPR/Cas9 genome editing on patient-derived iPSC to establish IRD-specific disease models enables researchers to study the distinct molecular effects associated with each IRD-related variant, extending beyond the mere absence of a protein as in KO murine models [ 82 , 83 ]. In this regard, the next steps in our research horizon include obtaining gene-edited iPSC-derived RPE cells to evaluate this matter and to future cell therapy assays as they seem to be the most promising alternatives for replacement therapies [ 84 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes

Puertas-Neyra,

Coco-Martin,

Hernandez-Rodriguez

et al. 2024

Stem Cell Res Ther

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Background Inherited retinal dystrophies (IRD) are one of the main causes of incurable blindness worldwide. IRD are caused by mutations in genes that encode essential proteins for the retina, leading to photoreceptor degeneration and loss of visual function. IRD generates an enormous global financial burden due to the lack of understanding of a significant part of its pathophysiology, molecular diagnosis, and the near absence of non-palliative treatment options. Patient-derived induced pluripotent stem cells (iPSC) for IRD seem to be an excellent option for addressing these questions, serving as exceptional tools for in-depth studies of IRD pathophysiology and testing new therapeutic approaches. Methods From a cohort of 8 patients with PROM1-related IRD, we identified 3 patients carrying the same variant (c.1354dupT) but expressing three different IRD phenotypes: Cone and rod dystrophy (CORD), Retinitis pigmentosa (RP), and Stargardt disease type 4 (STGD4). These three target patients, along with one healthy relative from each, underwent comprehensive ophthalmic examinations and their genetic panel study was expanded through clinical exome sequencing (CES). Subsequently, non-integrative patient-derived iPSC were generated and fully characterized. Correction of the c.1354dupT mutation was performed using CRISPR/Cas9, and the genetic restoration of the PROM1 gene was confirmed through flow cytometry and western blotting in the patient-derived iPSC lines. Results CES revealed that 2 target patients with the c.1354dupT mutation presented monoallelic variants in genes associated with the complement system or photoreceptor differentiation and peroxisome biogenesis disorders, respectively. The pluripotency and functionality of the patient-derived iPSC lines were confirmed, and the correction of the target mutation fully restored the capability of encoding Prominin-1 (CD133) in the genetically repaired patient-derived iPSC lines. Conclusions The c.1354dupT mutation in the PROM1 gene is associated to three distinct AR phenotypes of IRD. This pleotropic effect might be related to the influence of monoallelic variants in other genes associated with retinal dystrophies. However, further evidence needs to be provided. Future experiments should include gene-edited patient-derived iPSC due to its potential as disease modelling tools to elucidate this matter in question. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes

Puertas-Neyra,

Coco-Martin,

Hernandez-Rodriguez

et al. 2024

Stem Cell Res Ther

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Injury and Repair: Stem Cells and Retinal Transplantation

Tucker,

Young

2024

Reference Module in Neuroscience and Biobehavioral Psychology

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Sustained neurotrophic factor cotreatment enhances donor and host retinal ganglion cell survival in mice

Soucy,

Kriukov,

Oswald

et al. 2024

Preprint

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Retinal ganglion cells (RGCs) lack regenerative capacity in mammals, and their degeneration in glaucoma leads to irreversible blindness. Traditional RGC transplantation has been limited by poor survival rates of transplanted cells in the hostile microenvironment of a diseased retina. Our research identifies brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) as key elements in retinal development and RGC survival through in silico analysis of the single-cell transcriptome of developing human retinas. Although these factors are abundant during development, they diminish in adulthood. Here, we demonstrate that a slow-release formulation of BDNF and GDNF enhances RGC differentiation and survival in vitro and improves RGC transplantation outcomes in mouse models. This co-treatment increased survival and coverage of donor RGCs within the retina and enhanced neurite extension toward the optic nerve head. Lastly, this co-treatment showed neuroprotective effects on host RGCs, preserving retinal function in a model of optic neuropathy. Altogether, our findings suggest that manipulating the retinal microenvironment with slow-release neurotrophic factors holds promise in regenerative medicine for treating glaucoma and other optic neuropathies. This approach not only improves donor cell survival and integration but also provides a neuroprotective benefit to host cells, indicating a significant advancement for glaucoma therapies.

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Recent Progress in Retinal Pigment Epithelium Cell-Based Therapy for Retinal Disease

Cited by 3 publications

References 82 publications

Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes

Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes

Injury and Repair: Stem Cells and Retinal Transplantation

Sustained neurotrophic factor cotreatment enhances donor and host retinal ganglion cell survival in mice

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