Development of a<i>Pde6b</i>Gene Knockout Rat Model for Studies of Degenerative Retinal Diseases

Yeo, Joon Hyung; Jung, Bok Kyoung; Lee, Heuiran; Baek, In-Jeoung; Sung, Young Hoon; Shin, Hae Sol; Kim, Hong Kyung; Seo, Kyoung Yul; Lee, Joo Yong

doi:10.1167/iovs.18-25556

Cited by 27 publications

(19 citation statements)

References 37 publications

(35 reference statements)

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“…3a ). We generated a Pde6b knockout rat model as a retinal degeneration model that typically shows generalized retinal cell damage and reduced retinal thickness 3 weeks after postnatal development 18 . Cells were injected before the expected appearance of retinal damage at 2–3 weeks of age to decelerate retinal degeneration, and support the recovery of RPE cell and photoreceptor function.…”

Section: Resultsmentioning

confidence: 99%

“…In this study, we demonstrated for the first time that human iPSC (hiPSC)-derived retinal cells that can differentiate into both photoreceptors and RPE cells can efficiently rescue the degenerated host retina. Using a Pde6b knockout rat model, which is a novel model of RP established using CRISPR-Cpf1 technology 18 , we found that transplanted hiPSC-derived retinal cells can survive in the host retina for a long time and restore retinal function.…”

Section: Introductionmentioning

confidence: 99%

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Long-term effects of human induced pluripotent stem cell-derived retinal cell transplantation in Pde6b knockout rats

et al. 2021

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Retinal degenerative disorders, including age-related macular degeneration and retinitis pigmentosa (RP), are characterized by the irreversible loss of photoreceptor cells and retinal pigment epithelial (RPE) cells; however, the long-term effect of implanting both human induced pluripotent stem cell (hiPSC)-derived RPE and photoreceptor for retinal regeneration has not yet been investigated. In this study, we evaluated the long-term effects of hiPSC-derived RPE and photoreceptor cell transplantation in Pde6b knockout rats to study RP; cells were injected into the subretinal space of the right eyes of rats before the appearance of signs of retinal degeneration at 2–3 weeks of age. Ten months after transplantation, we evaluated the cells using fundus photography, optical coherence tomography, and histological evaluation, and no abnormal cell proliferation was observed. A relatively large number of transplanted cells persisted during the first 4 months; subsequently, the number of these cells decreased gradually. Notably, immunohistochemical analysis revealed that the hiPSC-derived retinal cells showed characteristics of both RPE cells and photoreceptors of human origin after transplantation. Functional analysis of vision by scotopic electroretinogram revealed significant preservation of vision after transplantation. Our study suggests that the transplantation of hiPSC-derived retinal cells, including RPE cells and photoreceptors, has a potential therapeutic effect against irreversible retinal degenerative diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Long-term effects of human induced pluripotent stem cell-derived retinal cell transplantation in Pde6b knockout rats

et al. 2021

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“…The expression of genes associated with the inflammatory response - such as Ifi44l , Serpina3n , S100a6 , Bcl3 , and Gfap - was also increased in the Prom1 -KO retina at P21. Conversely, the expression of genes related to RP or of those essential for retinal development and functional homeostasis - including Fscn2 (RP30) [19], Prph2 (RP7) [20], Nr2e3 (RP37) [21], Kcnv2 [22], Elovl2 [23], Pde6b (RD1) [24], and Ttc21b [25] - was down-regulated in the Prom1 -KO retina at P21 (supplementary table S3). GO term analysis revealed that several signalling pathways, including apoptotic (TNF) and infectious-related signal (Epstein-Barr virus infection) signals, were affected by the loss of Prom1 (figure 3 c ).…”

Section: Resultsmentioning

confidence: 99%

Light-dependent induction ofEdn2expression and attenuation of retinal pathology by endothelin receptor antagonists inProminin-1- deficient mice

Kobayashi

Shizuka

Shirai

et al. 2020

Preprint

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Retinitis pigmentosa (RP) and macular dystrophy (MD) are prevalent retinal degenerative diseases associated with gradual photoreceptor death. These diseases are often caused by genetic mutations that result in degeneration of the retina postnatally after it has fully developed. The Prominin-1 gene (Prom1) is a causative gene for RP and MD, and Prom1- knockout (KO) mice recapitulate key features of these diseases including light-dependent retinal degeneration and stenosis of retinal blood vessels. The mechanisms underlying progression of such degeneration have remained unknown, however. We here analysed early events associated with retinal degeneration in Prom1-KO mice. We found that photoreceptor cell death and glial cell activation occur between 2 and 3 weeks after birth. High-throughput analysis revealed that expression of the endothelin-2 gene (Edn2) was markedly up-regulated in the Prom1-deficient retina during this period. Expression of Edn2 was also induced by light stimulation in Prom1-KO mice that had been reared in the dark. Finally, treatment with endothelin receptor antagonists attenuated photoreceptor cell death, gliosis, and retinal vessel stenosis in Prom1-KO mice. Our findings suggest that inhibitors of endothelin signalling may delay the progression of RP and MD and therefore warrant further study as potential therapeutic agents for these diseases.

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“…For this reason, some orthologs of Cpf1 (Cas12a) are the most used after SpCas9, including Acidaminococcus sp. (AsCpf1) (Lee J. G. et al, 2019;Yeo et al, 2019) and Lachnospiraceae bacterium ND2006 (LbCpf1) (Lee J. G. et al, 2019).…”

Section: Crispr-cas Systemsmentioning

confidence: 99%

Advances in Genome Editing and Application to the Generation of Genetically Modified Rat Models

et al. 2021

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The rat has been extensively used as a small animal model. Many genetically engineered rat models have emerged in the last two decades, and the advent of gene-specific nucleases has accelerated their generation in recent years. This review covers the techniques and advances used to generate genetically engineered rat lines and their application to the development of rat models more broadly, such as conditional knockouts and reporter gene strains. In addition, genome-editing techniques that remain to be explored in the rat are discussed. The review also focuses more particularly on two areas in which extensive work has been done: human genetic diseases and immune system analysis. Models are thoroughly described in these two areas and highlight the competitive advantages of rat models over available corresponding mouse versions. The objective of this review is to provide a comprehensive description of the advantages and potential of rat models for addressing specific scientific questions and to characterize the best genome-engineering tools for developing new projects.

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Development of aPde6bGene Knockout Rat Model for Studies of Degenerative Retinal Diseases

Cited by 27 publications

References 37 publications

Long-term effects of human induced pluripotent stem cell-derived retinal cell transplantation in Pde6b knockout rats

Long-term effects of human induced pluripotent stem cell-derived retinal cell transplantation in Pde6b knockout rats

Light-dependent induction ofEdn2expression and attenuation of retinal pathology by endothelin receptor antagonists inProminin-1- deficient mice

Advances in Genome Editing and Application to the Generation of Genetically Modified Rat Models

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