USH2A variants causing retinitis pigmentosa or Usher syndrome provoke differential retinal phenotypes in disease-specific organoids

Sanjurjo-Soriano, Carla; Jimenez-Medina, Carla; Erkilic, Nejla; Cappellino, Luisina; Lefevre, Arnaud; Nagel-Wolfrum, Kerstin; Wolfrum, Uwe; Van Wijk, Erwin; Roux, Anne-Françoise; Meunier, Isabelle; Kalatzis, Vasiliki

doi:10.1016/j.xhgg.2023.100229

Cited by 12 publications

(8 citation statements)

References 64 publications

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“…For phalloidin staining, dissected eyes were fixed in 4% paraformaldehyde and labeled with Alexa Fluor 568–phalloidin (1/40, Molecular Probes). IF studies of human fibroblasts, iPSCs, EBs, RPE, and retinal organoids were performed as previously described ( 53 – 55 ). Primary antibodies were incubated at 4°C overnight, and secondary antibodies with 0.2 μg/mL Hoechst 33258 (MilliporeSigma) were incubated at room temperature for 1 hour ( Supplemental Table 6 ).…”

Section: Methodsmentioning

confidence: 99%

TBC1D32 variants disrupt retinal ciliogenesis and cause retinitis pigmentosa

Bocquet,

Borday,

Erkilic

et al. 2023

JCI Insight

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Retinitis pigmentosa (RP) is the most common inherited retinal disease (IRD) and is characterized by photoreceptor degeneration and progressive vision loss. We report 4 patients presenting with RP from 3 unrelated families with variants in TBC1D32 , which to date has never been associated with an IRD. To validate TBC1D32 as a putative RP causative gene, we combined Xenopus in vivo approaches and human induced pluripotent stem cell–derived (iPSC-derived) retinal models. Our data showed that TBC1D32 was expressed during retinal development and that it played an important role in retinal pigment epithelium (RPE) differentiation. Furthermore, we identified a role for TBC1D32 in ciliogenesis of the RPE. We demonstrated elongated ciliary defects that resulted in disrupted apical tight junctions, loss of functionality (delayed retinoid cycling and altered secretion balance), and the onset of an epithelial-mesenchymal transition–like phenotype. Last, our results suggested photoreceptor differentiation defects, including connecting cilium anomalies, that resulted in impaired trafficking to the outer segment in cones and rods in TBC1D32 iPSC-derived retinal organoids. Overall, our data highlight a critical role for TBC1D32 in the retina and demonstrate that TBC1D32 mutations lead to RP. We thus identify TBC1D32 as an IRD-causative gene.

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Section: Methodsmentioning

confidence: 99%

TBC1D32 variants disrupt retinal ciliogenesis and cause retinitis pigmentosa

Bocquet,

Borday,

Erkilic

et al. 2023

JCI Insight

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“…More recently, another group generated retinal organoids carrying mutations in USH2A . Retinal organoids were derived from either patients with Usher syndrome carrying the prominent homozygous c.2299delG or patients with non-syndromic RP harbouring compound heterozygous c.2299delG and c.2276G>T mutations [ 54 ]. Surprisingly, distinct retinal phenotypes emerged, depending on the origin of the patient-derived retinal organoids.…”

Section: Retinal Organoid Ciliopathy Modelsmentioning

confidence: 99%

Retinal Ciliopathies and Potential Gene Therapies: A Focus on Human iPSC-Derived Organoid Models

McDonald,

Wijnholds

2024

IJMS

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The human photoreceptor function is dependent on a highly specialised cilium. Perturbation of cilial function can often lead to death of the photoreceptor and loss of vision. Retinal ciliopathies are a genetically diverse range of inherited retinal disorders affecting aspects of the photoreceptor cilium. Despite advances in the understanding of retinal ciliopathies utilising animal disease models, they can often lack the ability to accurately mimic the observed patient phenotype, possibly due to structural and functional deviations from the human retina. Human-induced pluripotent stem cells (hiPSCs) can be utilised to generate an alternative disease model, the 3D retinal organoid, which contains all major retinal cell types including photoreceptors complete with cilial structures. These retinal organoids facilitate the study of disease mechanisms and potential therapies in a human-derived system. Three-dimensional retinal organoids are still a developing technology, and despite impressive progress, several limitations remain. This review will discuss the state of hiPSC-derived retinal organoid technology for accurately modelling prominent retinal ciliopathies related to genes, including RPGR, CEP290, MYO7A, and USH2A. Additionally, we will discuss the development of novel gene therapy approaches targeting retinal ciliopathies, including the delivery of large genes and gene-editing techniques.

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“…Patient-derived iPSC organoids were successfully used for the study of retinitis pigmentosa (RP), a congenital inherited retinal dystrophy characterized by many diseasecausing genetic mutations [232]. With the development and implementation of production techniques of iPSC-derived ROs, it was possible to evaluate the impact of mutations in different genes involved in the development and progression of this pathology [233][234][235]. The more common causes of RP are the mutations of the X-linked retinitis pigmentosa GTPase regulator (RPGR) gene.…”

Section: Organoids As Models For Retinal Degenerative Diseasesmentioning

confidence: 99%

Classical and Innovative Evidence for Therapeutic Strategies in Retinal Dysfunctions

Caruso,

Fields,

Rimondi

et al. 2024

IJMS

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The human retina is a complex anatomical structure that has no regenerative capacity. The pathogenesis of most retinopathies can be attributed to inflammation, with the activation of the inflammasome protein platform, and to the impact of oxidative stress on the regulation of apoptosis and autophagy/mitophagy in retinal cells. In recent years, new therapeutic approaches to treat retinopathies have been investigated. Experimental data suggest that the secretome of mesenchymal cells could reduce oxidative stress, autophagy, and the apoptosis of retinal cells, and in turn, the secretome of the latter could induce changes in mesenchymal cells. Other studies have evidenced that noncoding (nc)RNAs might be new targets for retinopathy treatment and novel disease biomarkers since a correlation has been found between ncRNA levels and retinopathies. A new field to explore is the interaction observed between the ocular and intestinal microbiota; indeed, recent findings have shown that the alteration of gut microbiota seems to be linked to ocular diseases, suggesting a gut–eye axis. To explore new therapeutical strategies for retinopathies, it is important to use proper models that can mimic the complexity of the retina. In this context, retinal organoids represent a good model for the study of the pathophysiology of the retina.

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USH2A variants causing retinitis pigmentosa or Usher syndrome provoke differential retinal phenotypes in disease-specific organoids

Cited by 12 publications

References 64 publications

TBC1D32 variants disrupt retinal ciliogenesis and cause retinitis pigmentosa

TBC1D32 variants disrupt retinal ciliogenesis and cause retinitis pigmentosa

Retinal Ciliopathies and Potential Gene Therapies: A Focus on Human iPSC-Derived Organoid Models

Classical and Innovative Evidence for Therapeutic Strategies in Retinal Dysfunctions

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