Modeling retinitis pigmentosa through patient-derived retinal organoids

Li, Yanping; Deng, Wen-Li; Jin, Zi‐Bing

doi:10.1016/j.xpro.2021.100438

Cited by 11 publications

(4 citation statements)

References 9 publications

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“…In recent research, organoids were used to evaluate the impact of several genes on RP development. In addition to RPGR [237], other genes have been studied such as pre-mRNA processing factor 31 homolog (PRPF31) [238,239] and Crumbs Cell Polarity Complex Component 1 (CRB1) [240,241]: in all these studies, CRISP-Cas9 gene editing was used to restore gene functionality. Other authors [242] have shown that the use of Adeno-associated viral vectors was also able to restore the phenotype of organoids derived from CRB1-mutated patients.…”

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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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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“…Significant efforts are directed toward developing new therapeutic strategies, implementing RO-based cell therapy and providing patient-derived ROs for gene therapy, thus promoting the development of personalized medicine [71]. The CRISPR-Cas9-mediated correction of the RPGR mutation restored gene expression and rescued the photoreceptor's structure and electrophysiological properties [72,73]. Treatment with PR3, a small molecule targeted to Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3), attenuates the increased Rhodopsin (RHO) expression and partially rescues the altered RHO trafficking in an iPSC-derived retinal organoid implemented from a patient with a copy number variation in the RHO gene [74].…”

Section: Retinitis Pigmentosa (Rp)mentioning

confidence: 99%

Advanced Cellular Models for Rare Disease Study: Exploring Neural, Muscle and Skeletal Organoids

Bombieri,

Corsi,

Trabetti

et al. 2024

IJMS

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Organoids are self-organized, three-dimensional structures derived from stem cells that can mimic the structure and physiology of human organs. Patient-specific induced pluripotent stem cells (iPSCs) and 3D organoid model systems allow cells to be analyzed in a controlled environment to simulate the characteristics of a given disease by modeling the underlying pathophysiology. The recent development of 3D cell models has offered the scientific community an exceptionally valuable tool in the study of rare diseases, overcoming the limited availability of biological samples and the limitations of animal models. This review provides an overview of iPSC models and genetic engineering techniques used to develop organoids. In particular, some of the models applied to the study of rare neuronal, muscular and skeletal diseases are described. Furthermore, the limitations and potential of developing new therapeutic approaches are discussed.

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“…To investigate in vitro tumorigenesis of Rb with patient-specific genomic background, we generated hROs from iPSC- RB1 m1/ wt and iPSC- RB1 m1/m2 using stepwise induction as described previously with slight modification ( 27 , 31 , 35 , 36 ) (Fig. 2A ).…”

Section: Tumor Differentiation In Hipscs-derived Hros With ...mentioning

confidence: 99%

Second hit impels oncogenesis of retinoblastoma in patient-induced pluripotent stem cell-derived retinal organoids: direct evidence for Knudson's theory

Wang

et al. 2022

PNAS Nexus

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Retinoblastoma (Rb) is a type of malignant tumor due to abnormal retinogenesis with biallelic mutations of the RB1 gene. Its pathogenesis has been proposed as a “two-mutation hypothesis” by Knudson since 1971; however, there remain some debates on disease onset sufficiency of the biallelic RB1 mutations. To obtain straightforward evidence for this hypothesis, we investigated that whether two-hit mutations of the RB1 gene drive tumorigenesis in a patient induced pluripotent stem cells (hiPSCs)-derived human retinal organoids (hROs) and that whether single allelic mutation hiPSCs-derived hROs exhibit molecular and cellular defects. We generated hiPSCs with a heterozygous germline mutation (RB1m1/wt) from a Rb patient. A second-allele RB1 gene mutation was knocked in to produce compound heterozygous mutations (RB1m1/m2) in the hiPSCs. These two hiPSC lines were independently developed into hROs through a stepwise differentiation. The hiPSC-RB1m1/m2 derived organoids demonstrated tumorigenesis in dishes, consistent with Rb profiles in spatiotemporal transcriptomes, in which developmentally photoreceptor fate-determining markers, CRX and OTX2, were highly expressed in hiPSC-RB1m1/m2 derived hROs. Additionally, ARR3+ maturing cone precursors were co-labeled with proliferative markers Ki67 or PCNA, in agreement with the consensus that human Rb is originated from maturing cone precursors. Finally, we demonstrated that retinal cells of hROs with monoallelic RB1 mutation were abnormal in molecular aspects due to its haploinsufficiency. In conclusion, this study provides straightforward supporting evidence in a way of reverse genetics for “two-hit hypothesis” in the Rb tumorigenesis and opens new avenues for development of early intervention and treatment of Rb.

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Modeling retinitis pigmentosa through patient-derived retinal organoids

Cited by 11 publications

References 9 publications

Classical and Innovative Evidence for Therapeutic Strategies in Retinal Dysfunctions

Classical and Innovative Evidence for Therapeutic Strategies in Retinal Dysfunctions

Advanced Cellular Models for Rare Disease Study: Exploring Neural, Muscle and Skeletal Organoids

Second hit impels oncogenesis of retinoblastoma in patient-induced pluripotent stem cell-derived retinal organoids: direct evidence for Knudson's theory

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