ORIGINAL RESEARCH article
Front. Cell. Neurosci.
Sec. Cellular Neuropathology
Volume 19 - 2025 | doi: 10.3389/fncel.2025.1635775
This article is part of the Research TopicRetinal Degenerative Diseases: Processes and Potential TreatmentsView all 7 articles
Establishment of human Leber’s hereditary optic neuropathy model using iPSC-derived retinal organoids
Provisionally accepted
- 1Gifu Pharmaceutical University, Gifu, Japan
- 2Nagara medical center, Gifu, Japan
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Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disease caused by mitochondrial DNA mutations, leading to central vision loss and retinal ganglion cell (RGC) degeneration. Progress in understanding LHON and developing treatments has been limited by the lack of human-like models. In this study, we aimed to establish a human retinal model of LHON using retinal organoids (ROs) from LHON patient-derived induced pluripotent stem cells (LHON-iPSCs). We first confirmed LHON-iPSCs were successfully differentiated into ROs (LHON-ROs). LHON-RO showed a reduction in RGC numbers and the density of neural axons. Additionally, both mitochondrial membrane potential and ATP production were decreased in LHON-RO. Finally, treatment with idebenone, the only approved therapeutic agent for LHON, improved RGC numbers in LHON-RO. This model replicates key clinical features of LHON, including RGC and axonal loss, and demonstrates idebenone’s therapeutic potential. Furthermore, a comprehensive analysis of the LHON-RO model revealed impaired mitophagy, suggesting novel therapeutic targets for LHON. Thus, the LHON-RO model offers a valuable platform for studying LHON pathogenesis and evaluating treatments.
Keywords: Retinal organoid, Leber's hereditary optic neuropathy, mitochondrial disease, In vitro disease modelling, mitophagy
Received: 27 May 2025; Accepted: 25 Aug 2025.
Copyright: © 2025 Aoshima, Takagi, Funato, Kuse, Nakamura and Shimazawa. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Masamitsu Shimazawa, Gifu Pharmaceutical University, Gifu, Japan
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