Modeling autosomal dominant optic atrophy using induced pluripotent stem cells and identifying potential therapeutic targets

Chen, Jing; Riazifar, Hamidreza; Guan, Min‐Xin; Huang, Taosheng

doi:10.1016/j.mito.2015.07.086

Cited by 9 publications

(11 citation statements)

References 29 publications

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“…Critical for the practical utility of the model, and unlike other monogenic diseases (Chen et al 2016), we did not observe any decline in self-renewal capacity of the MPSII patient-iPSC lines compared to controls. However, the cultures from the X-hemizygous male patient and, to some extent, from the X-heterozygous female patient expressed reduced ability to spontaneously form embryoid bodies.…”

Section: Discussionmentioning

confidence: 50%

Neural cells generated from human induced pluripotent stem cells as a model of CNS involvement in mucopolysaccharidosis type II

Rybová

Ledvinová

Sikora

et al. 2017

J of Inher Metab Disea

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Mucopolysaccharidosis type II (MPSII) is a rare X-linked lysosomal storage disorder caused by mutations in the iduronate-2-sulfatase (IDS) gene (IDS, Xq28). MPSII is characterized by skeletal deformities, hearing loss, airway obstruction, hepatosplenomegaly, cardiac valvular disease, and progressive neurological impairment. At the cellular level, IDS deficiency leads to lysosomal storage of glycosaminoglycans (GAGs), dominated by accumulation of dermatan and heparan sulfates. Human induced pluripotent stem cells (iPSC) represent an alternative system that complements the available MPSII murine model. Herein we report on the reprogramming of peripheral white blood cells from male and female MPSII patients into iPSC using a non-integrating protocol based on the Sendai virus vector system. We differentiated the iPSC lines into IDS deficient and GAG accumulating β-Tubulin III neurons, GFAP astrocytes, and CNPase oligodendrocytes. The lysosomal system in these cells displayed structural abnormalities reminiscent of those previously found in patient tissues and murine IDS deficient neuronal stem cells. Furthermore, quantitative determination of GAGs revealed a moderate increase in GAG levels in IDS deficient neurons and glia. We also tested the effects of recombinant IDS and found that the exogenous enzyme was internalized from the culture media and partially decreased the intracellular GAG levels in iPSC-derived neural cells; however, it failed to completely prevent accumulation of GAGs. In summary, we demonstrate that this human iPSC based model expresses the cellular and biochemical features of MPSII, and thus represents a useful experimental tool for further pathogenesis studies as well as therapy development and testing.

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Section: Discussionmentioning

confidence: 50%

Neural cells generated from human induced pluripotent stem cells as a model of CNS involvement in mucopolysaccharidosis type II

Rybová

Ledvinová

Sikora

et al. 2017

J of Inher Metab Disea

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“…[31][32][33][34] Likewise, RGCs with specific mutations, differentiated from patientderived hiPSCs, have provided models for optic atrophy and glaucoma. 35,36 The relative ease of creating specific mutations with CRISPR/Cas9 genome editing should make it possible to take advantage of the cell typespecific reporters in PGP1 when modeling genetic retinal diseases. 32 PGP1-derived retinal organoids will provide a platform to screen drugs to treat retinal damage.…”

Section: Discussionmentioning

confidence: 99%

Generation of a Retina Reporter hiPSC Line to Label Progenitor, Ganglion, and Photoreceptor Cell Types

Lam

Gutierrez

Rio‐Tsonis

et al. 2020

Trans. Vis. Sci. Tech.

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Early in mammalian eye development, VSX2, BRN3b, and RCVRN expression marks neural retinal progenitors (NRPs), retinal ganglion cells (RGCs), and photoreceptors (PRs), respectively. The ability to create retinal organoids from human induced pluripotent stem cells (hiPSC) holds great potential for modeling both human retinal development and retinal disease. However, no methods allowing the simultaneous, realtime monitoring of multiple specific retinal cell types during development currently exist. Methods: CRISPR/Cas9-mediated homology-directed repair (HDR) in hiPSCs facilitated the replacement of the VSX2 (Progenitor), BRN3b (Ganglion), and RCVRN (Photoreceptor) stop codons with sequences encoding a viral P2A peptide fused to Cerulean, green fluorescent protein, and mCherry reporter genes, respectively, to generate a triple transgenic reporter hiPSC line called PGP1. This was accomplished by co-electroporating HDR templates and sgRNA/Cas9 vectors into hiPSCs followed by antibiotic selection. Functional validation of the PGP1 hiPSC line included the ability to generate retinal organoids, with all major retinal cell types, displaying the expression of the three fluorescent reporters consistent with the onset of target gene expression. Disaggregated organoids were also analyzed by fluorescence-activated cell sorting and fluorescent populations were tested for the expression of the targeted gene. Results: Retinal organoids formed from the PGP1 line expressed appropriate fluorescent proteins consistent with the differentiation of NRPs, RGCs, and PRs. Organoids produced from the PGP1 line expressed transcripts consistent with the development of all major retinal cell types. Conclusions and Translational Relevance: The PGP1 line offers a powerful new tool to study retinal development, retinal reprogramming, and therapeutic drug screening.

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“…In the field of HONs, a few groups are already working on both LHON [235] and DOA [236]. Yang and colleagues generated hiPSC-derived RGCs and studied, in particular, the axonal transport [235], whereas Chen and colleagues investigated apoptosis in a similar setting, showing that excess apoptosis in OPA1 hiPSCs hampered the differentiation into RGCs [236]. This field is in its infancy and is about to rapidly expand accelerating drug screening and testing therapeutic strategies for HONs.…”

Section: Induced Pluripotent Stem Cellsmentioning

confidence: 99%

Therapeutic Options in Hereditary Optic Neuropathies

Amore

Romagnoli

Carbonelli

et al. 2020

Drugs

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Options for the effective treatment of hereditary optic neuropathies have been a long time coming. The successful launch of the antioxidant idebenone for Leber’s Hereditary Optic Neuropathy (LHON), followed by its introduction into clinical practice across Europe, was an important step forward. Nevertheless, other options, especially for a variety of mitochondrial optic neuropathies such as dominant optic atrophy (DOA), are needed, and a number of pharmaceutical agents, acting on different molecular pathways, are currently under development. These include gene therapy, which has reached Phase III development for LHON, but is expected to be developed also for DOA, whilst most of the other agents (other antioxidants, anti-apoptotic drugs, activators of mitobiogenesis, etc.) are almost all at Phase II or at preclinical stage of research. Here, we review proposed target mechanisms, preclinical evidence, available clinical trials with primary endpoints and results, of a wide range of tested molecules, to give an overview of the field, also providing the landscape of future scenarios, including gene therapy, gene editing, and reproductive options to prevent transmission of mitochondrial DNA mutations.

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Modeling autosomal dominant optic atrophy using induced pluripotent stem cells and identifying potential therapeutic targets

Cited by 9 publications

References 29 publications

Neural cells generated from human induced pluripotent stem cells as a model of CNS involvement in mucopolysaccharidosis type II

Neural cells generated from human induced pluripotent stem cells as a model of CNS involvement in mucopolysaccharidosis type II

Generation of a Retina Reporter hiPSC Line to Label Progenitor, Ganglion, and Photoreceptor Cell Types

Therapeutic Options in Hereditary Optic Neuropathies

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