RARE DISEASE
Leber hereditary optic neuropathy
Leber hereditary optic neuropathy
Leber hereditary optic neuropathy
Synonyms: LHON, Leber optic atrophy
Synonyms: LHON, Leber optic atrophy
Synonyms: LHON, Leber optic atrophy
Drug discovery
10
drugs
With orphan designations
Overview
Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder causing sudden, painless bilateral central vision loss, typically in adolescents/young adults. It results from mutations in mitochondrial DNA (e.g., MT-ND1, MT-ND4, MT-ND6), leading to retinal ganglion cell death and optic atrophy. While most carriers remain asymptomatic, affected individuals often progress to legal blindness (>20/200 acuity). LHON is the most common mitochondrial DNA disorder, with a male predominance [1][4][14][19].
Burden
~50% of affected males and 90% of females experience profound, permanent vision loss [4][14].
Associated with 2-fold increased mortality risk and higher rates of stroke, dementia, and cardiac defects [9][14].
Chronic disability impacts education/employment; 95% require lifelong low-vision support [4][16][19].
Therapies
Idebenone: Antioxidant approved in EU/USA; modest efficacy if started within 12 months of onset [4][18].
Gene therapy: GS011 (rAAV2/2-ND4) shows partial bilateral vision improvement in G11778A mutation trials [3][18].
Preventive measures: Mitochondrial replacement therapy for female carriers; avoidance of smoking/alcohol [8][13].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare ophthalmic disorders
Research Papers
533 drug discovery papers about Leber hereditary optic neuropathy, with 2 first-in-class and 24 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
533 drug discovery papers about Leber hereditary optic neuropathy, with 2 first-in-class and 24 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-04 | Implantable and Device-Based Nanomedicine Platforms in Glaucoma and Optic Neuropathies: A Narrative Review Bridging Pharmacology and Biomedical Engineering
Conventional treatment for neuro-ophthalmic disorders provides limited neuroprotection. This is due to the deficits for intraocular residence time, blood-ocular barriers, and neuroprotection. Contrasting compliance-dependent traditional approaches, recent advances have explored alternatives such as implantable and device-based nanomedicine platforms, to provide targeted, long-acting, and patient-friendly therapies. We searched for recent databases in “PubMed,” “Science Direct,” “Scopus,” “Medscape,” and ”Google Scholar” and evaluated recent developments in nano-enabled ocular implants and device-based nanomedicine platforms. This narrative review summarizes these developments of preclinical and translational studies to evaluate design innovation, assess biocompatibility. Recent investigations suggest that emerging implant and device technologies may provide sustained drug release, enhanced bioavailability, and a reduced intervention frequency. Significant results have been reported for glaucoma and Leber Hereditary Optic Neuropathy (LHON). This highlights a research gap in many other optic neuropathies (ischemic, toxic, infiltrative, infectious, compressive) as well as disorders for the neurological vision control. Advancements in pharmacology and biomedical engineering may help bridge the treatment gap in neuro-ophthalmology. This could facilitate more translational designs for the future. However, a major limitation is the absence of nano enabled implants and devices for many neuro-opthalamic disorders.
2026-08-03 | Late-Onset Leber Hereditary Optic Neuropathy: A Case Series of 16 Patients Diagnosed Above 65 Years of Age
Leber hereditary optic neuropathy (LHON) is a mitochondrial optic neuropathy that typically affects young adult males. Late-onset disease is rare and often underrecognised. We conducted a retrospective case series of patients aged > 65 years at onset of visual loss diagnosed with LHON between 2004 and 2025 at two tertiary referral centers in Belgium and the Netherlands. Demographics, genetic mutations, environmental and systemic risk factors, visual outcomes, and response to idebenone were analyzed. Best-corrected visual acuity was assessed at presentation, nadir, and >1 year after onset. Treatment response was defined according to criteria for clinically relevant recovery. Sixteen male patients were included, with a mean age of onset of 72.8 years. The most frequent mutation was MT-ND4 (m.11778 G > A), followed by MT-ND6 (m.14484T > C) and MT-ND1 (m.4135T > C). Seven patients reported a family history, none had a symptomatic mother. Visual loss was severe at presentation in most cases. Twelve patients received idebenone therapy, with clinically relevant recovery observed in half. However, final visual acuity remained poor in the majority. Risk factors were common, including smoking, high-risk alcohol use, diabetes mellitus, and glaucoma. Late-onset LHON is a clinically relevant but underrecognised phenotype, likely reflecting interplay between genetic susceptibility, cumulative exposures, comorbidities, and age-related mitochondrial dysfunction. Increased awareness is needed for timely diagnosis and management in elderly patients with unexplained optic neuropathy.
2026-07-31 | Systematic review of Leber's hereditary optic neuropathy - Clinical diagnosis, genetics overview and current concepts of treatment.
Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder, typically causing substantial, often permanent, central vision loss in young adults. It manifests as a subacute optic neuropathy, frequently progressing sequentially in both eyes, due to selective degeneration of retinal ganglion cells (RGCs). The condition is primarily associated with three mitochondrial DNA (mtDNA) point mutations-m.11778G>A, m.14484T>C, and m.3460G>A-located in complex I of the mitochondrial respiratory chain. These mutations impair oxidative phosphorylation, elevate reactive oxygen species (ROS), and trigger apoptosis of RGCs. Although historically considered untreatable, emerging therapies provide new prospects. Idebenone, a synthetic CoQ10 analog, is the first pharmacologic agent approved in Europe, demonstrating partial visual recovery in patients treated early by improving mitochondrial electron transport and reducing oxidative stress. Gene therapy using allotopic expression of ND4 via adeno-associated viral vectors (rAAV2/2-ND4) has shown improvement in both eyes even after unilateral injection. Advanced gene-editing techniques, such as zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), offer potential approaches for correcting heteroplasmic mutations. High-throughput genetic testing, including whole-genome sequencing and clinical exome analysis, enables precise identification of nuclear modifiers that influence LHON phenotypes, facilitating early diagnosis and intervention. Current clinical trials, including RESTORE and REFLECT, emphasize the importance of prompt treatment to optimize visual outcomes.
2026-07-27 | Bioenergetic dysfunction and inflammation in hiPSC-derived astrocytes from m.14484T>C Leber’s Hereditary Optic Neuropathy
Abstract Leber’s Hereditary Optic Neuropathy (LHON) is a maternally inherited mitochondrial disorder characterised by painless, progressive, and sequential visual failure. Most cases of LHON are driven by mitochondrial DNA mutations which cause dysfunction of respiratory Complex I, triggering retinal ganglion cell loss. Retinal ganglion cell degeneration in LHON is thought to be linked to reduced production of metabolic intermediates and adenosine triphosphate, and enhanced reactive oxygen species production. Thus, decades of research have focussed on LHON as a disease of the retinal ganglion cells, which has considerably improved our understanding of the pathology but has yielded few therapeutic interventions. In addition, some LHON-associated phenomena remain unclear. In particular, we still do not fully understand the mechanisms underlying the recorded phenomenon of spontaneous visual recovery, in which patients experience measurable increases in visual acuity following onset of LHON vision loss. Understanding this phenomenon may be critical for developing new therapeutic approaches for LHON. Moreover, the contribution of non-neuronal cell populations to LHON pathology remains poorly understood despite a growing appreciation for the roles played by these cells in other neurodegenerative conditions. Astrocytes are a highly heterogeneous group of glial cells, found throughout the central nervous system including the retina and optic nerve, and are well-known for their role as key homeostatic mediators. In recent years, our appreciation for the role played by astrocytes in neurodegenerative diseases has expanded considerably, and we are now aware that astrocytes undergo significant loss of their homeostatic functions in neurodegenerative disease, acting as key mediators of neuronal loss. Importantly, the contributions astrocytes make toward mediating LHON pathology and visual recovery remain unclear, and provide promising ground for potentially novel therapeutic angles and enhanced understanding of this complex pathology. Here, we leverage human iPSC-derived astrocytes from patients with the LHON m.14484T>C genotype, to explore the role astrocytes play in LHON pathology, stratifying cells by their visual recovery status. We report that astrocytes undergo significant morphological and bioenergetic compromise in LHON, and that differences between ‘recovery’ and ‘non-recovery’ astrocytes may explain individual capacity for visual recovery, potentially opening novel therapeutic approaches.
2026-07-15 | The Role of Apoptosis and Ferroptosis in Primary Mitochondrial Diseases: Mechanisms and Pathogenesis.
Mitochondrial diseases have traditionally been viewed as energy deficiencies, but current evidence positions mitochondria as central regulators of multiple cell death pathways. This review systematically analyzes the molecular mechanisms of apoptosis and ferroptosis in the context of both primary mitochondrial diseases-caused by mutations in mtDNA or nuclear DNA directly affecting oxidative phosphorylation-and secondary mitochondrial dysfunction associated with broader pathological conditions. Apoptosis is an energy-dependent process characterized by mitochondrial outer membrane permeabilization, cytochrome c release, and caspase cascade activation, whereas ferroptosis involves iron-dependent lipid peroxidation, glutathione depletion, and inactivation of glutathione peroxidase 4 (GPX4), leading to accumulation of oxidized phospholipids predominantly in endoplasmic reticulum and plasma membranes; mitochondrial ultrastructural changes-including volume reduction and cristae loss-represent characteristic morphological features of ferroptosis rather than its primary site of initiation. Key findings reveal that reactive oxygen species overproduction, disruption of reducing equivalent metabolism, iron dyshomeostasis, and calcium overload simultaneously prime cells for both death pathways. Cytochrome c, p53, and BCL-2 family proteins serve as integration hubs, with cardiolipin peroxidation and phospholipid composition influencing pathway switching. Tissue specificity is pronounced in primary mitochondrial diseases: retinal ganglion cells in Leber's hereditary optic neuropathy, cardiomyocytes in mtDNA-associated cardiomyopathies, and hepatocytes in mtDNA depletion syndromes exhibit distinct dominant death pathways. It should be noted, however, that for many conditions discussed, the evidence for ferroptosis involvement relies on indirect markers-such as lipid peroxidation products, decreased GPX4, and iron deposition-rather than on pharmacological rescue with ferrostatin-1 or liproxstatin-1 and rigorous exclusion of alternative death modalities; this limitation is discussed critically throughout the review. Diagnostic criteria combining morphological, biochemical, and pharmacological tools enable differentiation of death pathways. The review concludes that combined inhibition-using mitochondria-targeted antioxidants, GPX4 modulators, iron chelators, and mPTP blockers-together with personalized diagnostic algorithms offers the most promising therapeutic strategy. Understanding the apoptosis-ferroptosis crosstalk is essential for developing targeted interventions in mitochondrial diseases.
2026-08-04 | Implantable and Device-Based Nanomedicine Platforms in Glaucoma and Optic Neuropathies: A Narrative Review Bridging Pharmacology and Biomedical Engineering
Conventional treatment for neuro-ophthalmic disorders provides limited neuroprotection. This is due to the deficits for intraocular residence time, blood-ocular barriers, and neuroprotection. Contrasting compliance-dependent traditional approaches, recent advances have explored alternatives such as implantable and device-based nanomedicine platforms, to provide targeted, long-acting, and patient-friendly therapies. We searched for recent databases in “PubMed,” “Science Direct,” “Scopus,” “Medscape,” and ”Google Scholar” and evaluated recent developments in nano-enabled ocular implants and device-based nanomedicine platforms. This narrative review summarizes these developments of preclinical and translational studies to evaluate design innovation, assess biocompatibility. Recent investigations suggest that emerging implant and device technologies may provide sustained drug release, enhanced bioavailability, and a reduced intervention frequency. Significant results have been reported for glaucoma and Leber Hereditary Optic Neuropathy (LHON). This highlights a research gap in many other optic neuropathies (ischemic, toxic, infiltrative, infectious, compressive) as well as disorders for the neurological vision control. Advancements in pharmacology and biomedical engineering may help bridge the treatment gap in neuro-ophthalmology. This could facilitate more translational designs for the future. However, a major limitation is the absence of nano enabled implants and devices for many neuro-opthalamic disorders.
2026-08-03 | Late-Onset Leber Hereditary Optic Neuropathy: A Case Series of 16 Patients Diagnosed Above 65 Years of Age
Leber hereditary optic neuropathy (LHON) is a mitochondrial optic neuropathy that typically affects young adult males. Late-onset disease is rare and often underrecognised. We conducted a retrospective case series of patients aged > 65 years at onset of visual loss diagnosed with LHON between 2004 and 2025 at two tertiary referral centers in Belgium and the Netherlands. Demographics, genetic mutations, environmental and systemic risk factors, visual outcomes, and response to idebenone were analyzed. Best-corrected visual acuity was assessed at presentation, nadir, and >1 year after onset. Treatment response was defined according to criteria for clinically relevant recovery. Sixteen male patients were included, with a mean age of onset of 72.8 years. The most frequent mutation was MT-ND4 (m.11778 G > A), followed by MT-ND6 (m.14484T > C) and MT-ND1 (m.4135T > C). Seven patients reported a family history, none had a symptomatic mother. Visual loss was severe at presentation in most cases. Twelve patients received idebenone therapy, with clinically relevant recovery observed in half. However, final visual acuity remained poor in the majority. Risk factors were common, including smoking, high-risk alcohol use, diabetes mellitus, and glaucoma. Late-onset LHON is a clinically relevant but underrecognised phenotype, likely reflecting interplay between genetic susceptibility, cumulative exposures, comorbidities, and age-related mitochondrial dysfunction. Increased awareness is needed for timely diagnosis and management in elderly patients with unexplained optic neuropathy.
2026-07-31 | Systematic review of Leber's hereditary optic neuropathy - Clinical diagnosis, genetics overview and current concepts of treatment.
Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder, typically causing substantial, often permanent, central vision loss in young adults. It manifests as a subacute optic neuropathy, frequently progressing sequentially in both eyes, due to selective degeneration of retinal ganglion cells (RGCs). The condition is primarily associated with three mitochondrial DNA (mtDNA) point mutations-m.11778G>A, m.14484T>C, and m.3460G>A-located in complex I of the mitochondrial respiratory chain. These mutations impair oxidative phosphorylation, elevate reactive oxygen species (ROS), and trigger apoptosis of RGCs. Although historically considered untreatable, emerging therapies provide new prospects. Idebenone, a synthetic CoQ10 analog, is the first pharmacologic agent approved in Europe, demonstrating partial visual recovery in patients treated early by improving mitochondrial electron transport and reducing oxidative stress. Gene therapy using allotopic expression of ND4 via adeno-associated viral vectors (rAAV2/2-ND4) has shown improvement in both eyes even after unilateral injection. Advanced gene-editing techniques, such as zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), offer potential approaches for correcting heteroplasmic mutations. High-throughput genetic testing, including whole-genome sequencing and clinical exome analysis, enables precise identification of nuclear modifiers that influence LHON phenotypes, facilitating early diagnosis and intervention. Current clinical trials, including RESTORE and REFLECT, emphasize the importance of prompt treatment to optimize visual outcomes.
2026-07-27 | Bioenergetic dysfunction and inflammation in hiPSC-derived astrocytes from m.14484T>C Leber’s Hereditary Optic Neuropathy
Abstract Leber’s Hereditary Optic Neuropathy (LHON) is a maternally inherited mitochondrial disorder characterised by painless, progressive, and sequential visual failure. Most cases of LHON are driven by mitochondrial DNA mutations which cause dysfunction of respiratory Complex I, triggering retinal ganglion cell loss. Retinal ganglion cell degeneration in LHON is thought to be linked to reduced production of metabolic intermediates and adenosine triphosphate, and enhanced reactive oxygen species production. Thus, decades of research have focussed on LHON as a disease of the retinal ganglion cells, which has considerably improved our understanding of the pathology but has yielded few therapeutic interventions. In addition, some LHON-associated phenomena remain unclear. In particular, we still do not fully understand the mechanisms underlying the recorded phenomenon of spontaneous visual recovery, in which patients experience measurable increases in visual acuity following onset of LHON vision loss. Understanding this phenomenon may be critical for developing new therapeutic approaches for LHON. Moreover, the contribution of non-neuronal cell populations to LHON pathology remains poorly understood despite a growing appreciation for the roles played by these cells in other neurodegenerative conditions. Astrocytes are a highly heterogeneous group of glial cells, found throughout the central nervous system including the retina and optic nerve, and are well-known for their role as key homeostatic mediators. In recent years, our appreciation for the role played by astrocytes in neurodegenerative diseases has expanded considerably, and we are now aware that astrocytes undergo significant loss of their homeostatic functions in neurodegenerative disease, acting as key mediators of neuronal loss. Importantly, the contributions astrocytes make toward mediating LHON pathology and visual recovery remain unclear, and provide promising ground for potentially novel therapeutic angles and enhanced understanding of this complex pathology. Here, we leverage human iPSC-derived astrocytes from patients with the LHON m.14484T>C genotype, to explore the role astrocytes play in LHON pathology, stratifying cells by their visual recovery status. We report that astrocytes undergo significant morphological and bioenergetic compromise in LHON, and that differences between ‘recovery’ and ‘non-recovery’ astrocytes may explain individual capacity for visual recovery, potentially opening novel therapeutic approaches.
2026-07-15 | The Role of Apoptosis and Ferroptosis in Primary Mitochondrial Diseases: Mechanisms and Pathogenesis.
Mitochondrial diseases have traditionally been viewed as energy deficiencies, but current evidence positions mitochondria as central regulators of multiple cell death pathways. This review systematically analyzes the molecular mechanisms of apoptosis and ferroptosis in the context of both primary mitochondrial diseases-caused by mutations in mtDNA or nuclear DNA directly affecting oxidative phosphorylation-and secondary mitochondrial dysfunction associated with broader pathological conditions. Apoptosis is an energy-dependent process characterized by mitochondrial outer membrane permeabilization, cytochrome c release, and caspase cascade activation, whereas ferroptosis involves iron-dependent lipid peroxidation, glutathione depletion, and inactivation of glutathione peroxidase 4 (GPX4), leading to accumulation of oxidized phospholipids predominantly in endoplasmic reticulum and plasma membranes; mitochondrial ultrastructural changes-including volume reduction and cristae loss-represent characteristic morphological features of ferroptosis rather than its primary site of initiation. Key findings reveal that reactive oxygen species overproduction, disruption of reducing equivalent metabolism, iron dyshomeostasis, and calcium overload simultaneously prime cells for both death pathways. Cytochrome c, p53, and BCL-2 family proteins serve as integration hubs, with cardiolipin peroxidation and phospholipid composition influencing pathway switching. Tissue specificity is pronounced in primary mitochondrial diseases: retinal ganglion cells in Leber's hereditary optic neuropathy, cardiomyocytes in mtDNA-associated cardiomyopathies, and hepatocytes in mtDNA depletion syndromes exhibit distinct dominant death pathways. It should be noted, however, that for many conditions discussed, the evidence for ferroptosis involvement relies on indirect markers-such as lipid peroxidation products, decreased GPX4, and iron deposition-rather than on pharmacological rescue with ferrostatin-1 or liproxstatin-1 and rigorous exclusion of alternative death modalities; this limitation is discussed critically throughout the review. Diagnostic criteria combining morphological, biochemical, and pharmacological tools enable differentiation of death pathways. The review concludes that combined inhibition-using mitochondria-targeted antioxidants, GPX4 modulators, iron chelators, and mPTP blockers-together with personalized diagnostic algorithms offers the most promising therapeutic strategy. Understanding the apoptosis-ferroptosis crosstalk is essential for developing targeted interventions in mitochondrial diseases.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
10 orphan drug designations for Leber hereditary optic neuropathy, including 1 approved therapy.
10 orphan drug designations for Leber hereditary optic neuropathy, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
oral small-molecule modulator targeted NQO1 | small molecules | FDA | 2026-05-21 | — | Curome Biosciences Co., Ltd. |
Adeno-associated virus vector serotype 2 expressing the human MT-ND4 codon-optimised gene | gene therapies | EMA | 2022-01-14 | — | PPD Bulgaria EOOD |
recombinant adeno-associated virus serotype 2 containing human mitochondrial ND1 codon optimized gene (rAAV2-ND1) | gene therapies | FDA | 2022-01-13 | — | Neurophth Therapeutics, Inc. |
[10-(4,5-dimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)decyl](triphenyl)phosphonium bromide | small molecules | FDA | 2021-11-04 | — | Mitotech S.A. |
Recombinant Human Adeno-Associated Virus Serotype 2 Containing Human Mitochondrial ND4 gene (rAAV2-ND4) | gene therapies | FDA | 2020-09-22 | — | Neurophth Therapeutics, Inc. |
elamipretide | small molecules | FDA | 2018-04-02 | — | Stealth BioTherapeutics Inc. |
lenadogene nolparvovec | gene therapies | FDA | 2013-11-20 | — | Gensight Biologics |
Adeno-associated viral vector containing the human NADH dehydrogenase 4 gene | gene therapies | EMA | 2011-05-13 | — | GenSight- Biologics |
Idebenone [Raxone] | small molecules | EMA | 2007-02-15 | 2015-09-10 | Chiesi Farmaceutici S.p.A. |
idebenone | small molecules | FDA | 2006-10-31 | — | Chiesi Farmaceutici S.p.A. |
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