Recreating pathophysiology of CLN2 disease and demonstrating reversion by TPP1 gene therapy in hiPSCs-derived retinal organoid and retina-on-chip
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ABSTRACT:
PROVIDER: PRJNA1022020 | ENA |
REPOSITORIES: ENA
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Project description:Mutations in tripeptidyl peptidase 1 (TPP1) gene lead to late infantile neuronal ceroid lipofuscinosis CLN2, characterized by lysosomal accumulation of lipofuscins predominantly found in brain and retina. The ocular phenotype is characterized by bilateral outer retinal degeneration that leads to complete vision loss. CLN2 animal models struggle in recapitulating the retinal phenotype observed in patients. Here, we leveraged human induced pluripotent stem cell (hiPSC)-derived retinal organoids (ROs), retinal pigmented epithelial (RPE) cells, and retina-on-chip (RoC) technologies to model CLN2 disease in vitro in patient-specific microphysiological models of the human retina. Using these models, we were able to recreate the major clinical histological hallmark of CLN2 patients, namely the accumulation of lipofuscins containing subunit C of mitochondrial ATP synthase (SCMAS) and lipids mainly in the outer retina. Furthermore, single-cell RNA-sequencing of CLN2 ROs revealed a dysregulation of translational and mitochondrial function in cones. Finally, we demonstrate that an adeno-associated virus (AAV)-mediated TPP1 gene therapy was able to restore TPP1 expression and could decrease and even prevent SCMAS accumulations. In summary, our study produced novel human-relevant microphysiological retinal disease models, uncovered new mechanisms of CLN2 pathophysiology in the human retina, and demonstrated the immense potential of AAV9.hCLN2 gene therapy for CLN2 disease potentially treating and even curing blindness of affected individuals.
2025-07-25 | GSE297954 | GEO
Project description:Mutations in tripeptidyl peptidase 1 (TPP1) gene lead to late infantile neuronal ceroid lipofuscinosis CLN2, characterized by lysosomal accumulation of lipofuscins predominantly found in brain and retina. The ocular phenotype is characterized by bilateral outer retinal degeneration that leads to complete vision loss. CLN2 animal models struggle in recapitulating the retinal phenotype observed in patients. Here, we leveraged human induced pluripotent stem cell (hiPSC)-derived retinal organoids (ROs), retinal pigmented epithelial (RPE) cells, and retina-on-chip (RoC) technologies to model CLN2 disease in vitro in patient-specific microphysiological models of the human retina. Using these models, we were able to recreate the major clinical histological hallmark of CLN2 patients, namely the accumulation of lipofuscins containing subunit C of mitochondrial ATP synthase (SCMAS) and lipids mainly in the outer retina. Furthermore, single-cell RNA-sequencing of CLN2 ROs revealed a dysregulation of translational and mitochondrial function in cones. Finally, we demonstrate that an adeno-associated virus (AAV)-mediated TPP1 gene therapy was able to restore TPP1 expression and could decrease and even prevent SCMAS accumulations. In summary, our study produced novel human-relevant microphysiological retinal disease models, uncovered new mechanisms of CLN2 pathophysiology in the human retina, and demonstrated the immense potential of AAV9.hCLN2 gene therapy for CLN2 disease potentially treating and even curing blindness of affected individuals.
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Project description:The retina is a delicate tissue that detects light, converts photochemical energy into neural signals, and transmits the signals to the visual cortex of the brain. A detailed protein inventory of the proteome of the normal human eye may provide a foundation for new investigations into both the physiology of the retina and the pathophysiology of retinal diseases. To provide an inventory, proteins were extracted from five retinas of normal eyes and fractionated using SDS-PAGE. After in-gel digestion, peptides were analyzed in duplicate using LC-MS/MS on an Orbitrap Elite mass spectrometer. A total of 3,436 non-redundant proteins were identified in the human retina, including 20 unambiguous protein isoforms, of which 8 have not previously been demonstrated to exist at the protein level. The proteins identified in the retina included most of the enzymes involved in the visual cycle and retinoid metabolism. One hundred and fifty-eight proteins that have been associated with age-related macular degeneration were identified in the retina. The MS proteome database of the human retina may serve as a valuable resource for future investigations of retinal biology and disease.
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