Modeling and Rescue of RP2 Retinitis Pigmentosa Using iPSC-Derived Retinal Organoids

Lane, Amelia; Jovanović, Katarina; Shortall, Ciara; Ottaviani, Daniele; Panes, Anna Brugulat; Schwarz, Nele; Guarascio, Rosellina; Hayes, Matthew J.; Palfi, Arpad; Chadderton, Naomi; Farrar, G. Jane; Hardcastle, Alison J.; Cheetham, Michael E.

doi:10.1016/j.stemcr.2020.05.007

Cited by 123 publications

(113 citation statements)

References 48 publications

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“…Recently, genome-edited cell lines have been used to generate models of retinal disease in the dish ( Capowski et al, 2014 ; Zheng et al, 2020 ). Patient-derived iPSC lines with disease-causing mutations have been corrected to create ideal isogenic control lines that can be differentiated in parallel to validate disease phenotypes ( Lam et al, 2020 ; Lane et al, 2020 ; VanderWall et al, 2020 ). Edited cell lines are also valuable to test novel regulators of development and disease ( Buskin et al, 2018 ; Deng et al, 2018 ; Eldred et al, 2018 ; Phillips et al, 2014 ).…”

Section: The Development Of Cell Types Within Retinal Organoidsmentioning

confidence: 99%

Retinal organoids: a window into human retinal development

2020

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Retinal development and maturation are orchestrated by a series of interacting signalling networks that drive the morphogenetic transformation of the anterior developing brain. Studies in model organisms continue to elucidate these complex series of events. However, the human retina shows many differences from that of other organisms and the investigation of human eye development now benefits from stem cell-derived organoids. Retinal differentiation methods have progressed from simple 2D adherent cultures to self-organising micro-physiological systems. As models of development, these have collectively offered new insights into the previously unexplored early development of the human retina and informed our knowledge of the key cell fate decisions that govern the specification of light-sensitive photoreceptors. Although the developmental trajectories of other retinal cell types remain more elusive, the collation of omics datasets, combined with advanced culture methodology, will enable modelling of the intricate process of human retinogenesis and retinal disease in vitro.

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Section: The Development Of Cell Types Within Retinal Organoidsmentioning

confidence: 99%

Retinal organoids: a window into human retinal development

2020

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“…Using material derived from patients, organoids modelling for example cystic fibrosis [ 70 , 71 ], Rett syndrome [ 72 ], α1-antitrypsin deficiency [ 73 ], polycystic kidney disease [ 74 , 75 ], or Hermansky-Pudlak syndrome [ 76 ] have already been established. Furthermore, a variety of different disease modelling organoids have been generated using hiPSCs derived from patients carrying specific diseases-associated mutations: Among many others, retinal organoids modelling retinitis pigmentosa [ 77 ], colon organoids modelling colorectal cancer [ 78 ], and hiPSC-derived intestinal organoids from cystic fibrosis patients [ 79 ] were established. Patient-specific hiPSC-derived brain organoids can be used to model for example lissencephaly [ 80 ] or Down syndrome [ 81 ].…”

Section: Human Organoidsmentioning

confidence: 99%

Human Embryo Models and Drug Discovery

Rosner¹,

Reithofer²,

Fink³

et al. 2021

IJMS

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For obvious reasons, such as, e.g., ethical concerns or sample accessibility, model systems are of highest importance to study the underlying molecular mechanisms of human maladies with the aim to develop innovative and effective therapeutic strategies. Since many years, animal models and highly proliferative transformed cell lines are successfully used for disease modelling, drug discovery, target validation, and preclinical testing. Still, species-specific differences regarding genetics and physiology and the limited suitability of immortalized cell lines to draw conclusions on normal human cells or specific cell types, are undeniable shortcomings. The progress in human pluripotent stem cell research now allows the growth of a virtually limitless supply of normal and DNA-edited human cells, which can be differentiated into various specific cell types. However, cells in the human body never fulfill their functions in mono-lineage isolation and diseases always develop in complex multicellular ecosystems. The recent advances in stem cell-based 3D organoid technologies allow a more accurate in vitro recapitulation of human pathologies. Embryoids are a specific type of such multicellular structures that do not only mimic a single organ or tissue, but the entire human conceptus or at least relevant components of it. Here we briefly describe the currently existing in vitro human embryo models and discuss their putative future relevance for disease modelling and drug discovery.

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“…Another study showed, using AAV-CMV-GFP constructs, a more efficient retinal organoid transduction at DD220 especially in MGC with AAV5 or ShH10Y445F capsids in comparison with AAV9 (Quinn et al, 2019a). Recently, Lane et al (2020) demonstrate efficient PRCs transduction in DD140 retinal organoids using an AAV5 packaged with the CAG promoter. Moreover, AAV5-mediated gene augmentation with human RP2 was able to rescue the degeneration found in RP2 KO retinal organoids by preventing ONL thinning and restoring rhodopsin expression (Lane et al, 2020).…”

Section: Gene Augmentation Strategies For Crb1 Retinal Dystrophiesmentioning

confidence: 99%

“…Recently, Lane et al (2020) demonstrate efficient PRCs transduction in DD140 retinal organoids using an AAV5 packaged with the CAG promoter. Moreover, AAV5-mediated gene augmentation with human RP2 was able to rescue the degeneration found in RP2 KO retinal organoids by preventing ONL thinning and restoring rhodopsin expression (Lane et al, 2020). Therefore, testing CRB1-or CRB2-expressing vectors in retinal organoids will aid in the discovery of CRB gene therapy treatment for CRB1-related retinal dystrophies in patients.…”

Section: Gene Augmentation Strategies For Crb1 Retinal Dystrophiesmentioning

confidence: 99%

Research Models and Gene Augmentation Therapy for CRB1 Retinal Dystrophies

2020

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Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are inherited degenerative retinal dystrophies with vision loss that ultimately lead to blindness. Several genes have been shown to be involved in early onset retinal dystrophies, including CRB1 and RPE65. Gene therapy recently became available for young RP patients with variations in the RPE65 gene. Current research programs test adeno-associated viral gene augmentation or editing therapy vectors on various disease models mimicking the disease in patients. These include several animal and emerging human-derived models, such as human-induced pluripotent stem cell (hiPSC)-derived retinal organoids or hiPSC-derived retinal pigment epithelium (RPE), and human donor retinal explants. Variations in the CRB1 gene are a major cause for early onset autosomal recessive RP with patients suffering from visual impairment before their adolescence and for LCA with newborns experiencing severe visual impairment within the first months of life. These patients cannot benefit yet from an available gene therapy treatment. In this review, we will discuss the recent advances, advantages and disadvantages of different CRB1 human and animal retinal degeneration models. In addition, we will describe novel therapeutic tools that have been developed, which could potentially be used for retinal gene augmentation therapy for RP patients with variations in the CRB1 gene.

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Modeling and Rescue of RP2 Retinitis Pigmentosa Using iPSC-Derived Retinal Organoids

Cited by 123 publications

References 48 publications

Retinal organoids: a window into human retinal development

Retinal organoids: a window into human retinal development

Human Embryo Models and Drug Discovery

Research Models and Gene Augmentation Therapy for CRB1 Retinal Dystrophies

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