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:
categories:
Small molecules
small molecules
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.
2026-07-27 | 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.
2026-07-07 | When LHON Mimics Demyelination: Area Postrema Syndrome in Biallelic DNAJC30 Variants
Introduction: Biallelic pathogenic variants in DNAJC30 cause an autosomal recessive form of Leber hereditary optic neuropathy (LHONAR1), traditionally considered a mitochondrially transmitted disorder. The phenotypic spectrum of diseases linked to DNAJC30 includes isolated optic neuropathy, Leigh syndrome spectrum (LSS), and atypical LHON-plus. Case description: Here, we report a 13-year-old boy presenting symptoms of area postrema syndrome (APS), with recurrent vomiting, vertigo, nystagmus, and subacute visual deterioration with central scotoma. Ophthalmological examination revealed bilateral papilledema with telangiectatic vessels, while visual evoked potentials demonstrated severe bilateral optic pathway dysfunction. Brain magnetic resonance imaging (MRI) showed T2/FLAIR hyperintense lesions involving the area postrema and enhancement of the optic nerves, strongly suggesting seronegative neuromyelitis optica spectrum disorder (NMOSD). Extensive immunological and cerebrospinal fluid studies, including anti-aquaporin-4 (AQP4) and anti-MOG antibodies, were negative. High-dose corticosteroids and intravenous immunoglobulins resulted in only transient and incomplete improvement, followed by further visual decline. Additionally, laboratory tests detected elevated lactate plasma levels. Hence, whole-exome sequencing was performed, which identified a homozygous pathogenic DNAJC30 c.152A>G, p.(Tyr51Cys) variant, associated with LHONAR1. After initiation of idebenone therapy, the patient showed significant improvement in visual function, normalization of lactate levels, and complete resolution of the brainstem lesions on follow-up MRI. Conclusions: This case further expands the neuro-ophthalmic spectrum associated with DNAJC30 variants and suggests that DNAJC30-related disease may closely mimic seronegative NMOSD. We highlight that early genetic diagnosis is essential, as recognition of this mitochondrial etiology enables targeted therapy and may substantially improve clinical outcomes.
2026-06-27 | Clinical development in primary mitochondrial diseases at a translational inflection point: Lessons, mechanisms, and emerging therapeutic strategies.
Clinical development for primary mitochondrial diseases (PMDs) has spanned more than two decades, yet therapeutic success remains limited. In this Review, we provide a comprehensive, pharmacology-focused analysis of the PMD clinical trial landscape and identify key mechanistic and translational determinants underlying recent progress. A systematic survey of ClinicalTrials.gov covering January 2010 to April 2026 identified 159 registered studies across PMD subtypes after deduplication, including 110 interventional trials. Progress has been constrained by marked genetic and phenotypic heterogeneity, small and geographically dispersed patient populations, and the lack of validated pharmacodynamic and disease-specific endpoints. Consequently, several well-designed late-stage trials have yielded negative or inconclusive outcomes, and regulatory approvals have historically been scarce. Recent advances, however, indicate a shift in trajectory. Four therapies have achieved regulatory authorization, including idebenone for Leber hereditary optic neuropathy, taurine for MELAS, and recent FDA approvals of doxecitine and doxribtimine (Kygevvi) for thymidine kinase 2 deficiency and elamipretide (FORZINITY) for Barth syndrome. These successes share a convergent translational framework integrating mechanism-based pharmacology, genotype-driven patient selection, and biologically aligned endpoints. Clinical activity has also accelerated, with approximately half of PMD interventional trials initiated since 2020 and 50 studies currently active or recruiting. Emerging strategies include NAD⁺ augmentation, soluble guanylate cyclase stimulation, mTOR modulation, gene therapies, and heteroplasmy-targeting approaches. Collectively, these advances mark an emerging inflection point and suggest a path toward greater regulatory success in the coming decade.
gene therapies
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.
2026-07-31 | 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.
2026-05-14 | Gene Therapy for Leber Hereditary Optic Neuropathy (LHON): A Systematic Review and Meta-Analysis.
LHON is a rare mitochondrial disease causing bilateral vision loss, most commonly due to the m.11778G>A mutation. rAAV2/2-ND4 gene therapy is a potential disease-modifying treatment. Systematic review and meta-analysis of three RCTs (RESCUE, REVERSE, REFLECT) including 175 patients. Gene therapy significantly improved best-corrected visual acuity but did not significantly increase responder rates. Adverse events were mostly mild ocular inflammation, with no treatment-related mortality. rAAV2/2-ND4 is a moderately effective and safe treatment for LHON, though long-term outcomes and predictors of response remain unclear.
2026-04-16 | LEBER'S HEREDITARY OPTIC NEUROPATHY (LHON): A GLOBAL COMPARISON WITH SPECIAL EMPHASIS ON INDIA
Leber’s hereditary optic neuropathy (LHON) is a rare mitochondrial genetic disorder, which is characterized by acute to subacute painless loss of central vision in young adult males. It is caused by a point mutation of mitochondrial DNA, which includes m. 11778G>A, m.3460G>A, m. and m. 14484T>C, resulting in retinal ganglion cell loss due to optic neuropathy. The prevalence of LHON worldwide is considerably variable due to genetic predisposition, geographical factors, and technical factors. In India, LHON is believed to be underdiagnosed and underreported compared to Western and East Asian nations. Also, Limited Availability of physician awareness in LHON can lead to a delay in diagnosis. Data collected in India shows a relatively high prevalence of sporadic cases and different mutations, of which m. 11778G>a is the predominant mutation. Environmental factors such as alcohol and cigarette use, nutritional deficiencies, and toxic exposures could also affect LHON and impact affected individuals in India. By contrast, the prevalence of better epidemiological data is observed in Japan, China, Europe, and the United States owing to the presence of genetic screening programs and patient registries. Japan has a relatively higher prevalence of m.11778G>A mutations, and European cohorts have a better rate of visual recovery owing to early intervention and treatment with odobenine and novel gene therapies based on adeno-associated virus vectors. In general, though LOHN is a worldwide phenomenon, there are considerable variations between Indian and international cases recording diagnosis, handling, and advancement in research. Enhancement in genetic lab facilities, awareness among doctors, and availability of new treatment are needed for improving the present status of LOHN in India.
2026-03-18 | Visual Loss from Leber's Optic Neuropathy Presenting in a 76-Year-Old Man with the 14484 Mutations.
Leber's Hereditary Optic Neuropathy (LHON) is an important hereditary optic neuropathy that typically causes bilateral visual loss, predominantly in male patients. While it usually manifests in young adults, it can uncommonly present in older individuals without a family history, potentially leading to diagnostic confusion. The mechanisms underlying why some individuals with these mutations develop optic neuropathy while others remain asymptomatic are still under investigation. Factors such as heteroplasmy, epigenetic modifications, and environmental triggers, including alcohol consumption, are thought to contribute. However, the exact triggers that convert carriers into symptomatic individuals remain poorly understood, with cigarette smoking and alcohol intake being potential contributors. The purpose of this paper is to describe a 76-year-old patient who experienced, painless bilateral visual loss progressing over 4 weeks. Despite extensive evaluation, including imaging, blood tests, and genetic testing, a mitochondrial mutation (T14484C) associated with LHON was identified. Although LHON is rare, especially in the elderly, and usually presents in younger males, this case highlights the need for clinicians to consider LHON as a potential diagnosis in older patients presenting with unexplained visual loss.
oligonucleotides
2025-11-02 | Mitochondrial genome microhomology-mediated editing by donor DNA delivery into mitochondria in human cells
Summary Mutations in the mitochondrial DNA (mtDNA) are associated with severe human diseases, lacking efficient therapies. Direct correction of mtDNA mutations may offer a cure for such diseases. We propose a novel strategy based on double-stranded DNA (dsDNA) oligonucleotide delivery into mitochondria and intrinsic microhomology-mediated end joining (MMEJ) for mtDNA editing. This strategy enables introduction of multiple predefined nucleotide changes in mtDNA. For this, the presence of MMEJ activity in the human mitochondrial lysates was confirmed. 49 bp DNA oligonucleotide duplexes, fused to an RNA hairpin previously identified as a mitochondrial import signal, were delivered into the mitochondria of cultured human cells. Delivery of these donor dsDNA molecules, homological to an ND4 site of mtDNA and bearing designed nucleotide changes, led to a low but statistically significant introduction of the designed nucleotide changes into mtDNA. Donor dsDNA delivery combined with the CRISPR/mito-AsCas12a system also resulted in a statistically significant number of an expected concomitant change of five nucleotides distributed across a 16-nucleotide ND4 site of the mitochondrial genome. The proposed strategy may become an efficient mtDNA editing tool suitable for the correction of near-homoplasmic mutations such as Leber’s Hereditary Optic Neuropathy (LHON)-associated mutations in the ND4 gene of mtDNA.
2024-03-06 | Dysregulation of the circRNA_0087207/miR-548c-3p/PLSR1-TGFB2 axis in Leber hereditary optic neuropathy in vitro.
Leber hereditary optic neuropathy (LHON) is mainly the degeneration of retinal ganglion cells (RGCs) associated with high apoptosis and reactive oxygen species (ROS) levels, which is accepted to be caused by the mutations in the subunits of complex I of the mitochondrial electron transport chain. The treatment is still infant while efforts of correcting genes or using antioxidants do not bring good and consistent results. Unaffected carrier carries LHON mutation but shows normal phenotype, suggesting that the disease's pathogenesis is complex, in which secondary factors exist and cooperate with the primary complex I dysfunction. Using LHON patient-specific induced pluripotent stem cells (iPSCs) as the in vitro disease model, we previously demonstrated that circRNA_0087207 had the most significantly higher expression level in the LHON patient-iPSC-derived RGCs compared with the unaffected carrier-iPSC-derived RGCs. To elaborate the underlying pathologies regulated by circRNA_008720 mechanistically, bioinformatics analysis was conducted and elucidated that circRNA_0087207 could act as a sponge of miR-548c-3p and modulate PLSCR1/TGFB2 levels in ND4 mutation-carrying LHON patient-iPSC-derived RGCs. Using LHON iPSC-derived RGCs as the disease-based platform, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis on targeted mRNA of miR-548c-3p showed the connection with apoptosis, suggesting downregulation of miR548c-3p contributes to the apoptosis of LHON patient RGCs. We showed that the downregulation of miR548c-3p plays a critical role in modulating cellular dysfunction and the apoptotic program of RGCs in LHON.
2023-08-01 | Mitochondrial transport of catalytic RNAs and targeting of the organellar transcriptome in human cells
Abstract Mutations in the small genome present in mitochondria often result in severe pathologies. Different genetic strategies have been explored, aiming to rescue such mutations. A number of these strategies were based on the capacity of human mitochondria to import RNAs from the cytosol and designed to repress the replication of the mutated genomes or to provide the organelles with wild-type versions of mutant transcripts. However, the mutant RNAs present in mitochondria turned out to be an obstacle to therapy and little attention has been devoted so far to their elimination. Here, we present the development of a strategy to knockdown mitochondrial RNAs in human cells using the transfer RNA-like structure of Brome mosaic virus or Tobacco mosaic virus as a shuttle to drive trans-cleaving ribozymes into the organelles in human cell lines. We obtained a specific knockdown of the targeted mitochondrial ATP6 mRNA, followed by a deep drop in ATP6 protein and a functional impairment of the oxidative phosphorylation chain. Our strategy provides a powerful approach to eliminate mutant organellar transcripts and to analyse the control and communication of the human organellar genetic system.
2022-03-28 | Retinal Circular RNA hsa_circ_0087207 Expression Promotes Apoptotic Cell Death in Induced Pluripotent Stem Cell-Derived Leber’s Hereditary Optic Neuropathy-like Models
Backgrounds: Leber's hereditary optic neuropathy (LHON) is known as an inherited retinal disorder characterized by the bilateral central vision loss and degeneration of retinal ganglion cells (RGCs). Unaffected LHON carriers are generally asymptomatic, suggesting that certain factors may contribute to the disease manifestations between carriers and patients who carry the same mutated genotypes. Methods: We first aimed to establish the iPSC-differentiated RGCs from the normal healthy subject, the carrier, and the LHON patient and then compared the differential expression profile of circular RNAs (CircRNAs) among RGCs from these donors in vitro. We further overexpressed or knocked down the most upregulated circRNA to examine whether this circRNA contributes to the distinct phenotypic manifestations between the carrier- and patient-derived RGCs. Results: iPSCs were generated from the peripheral blood cells from the healthy subject, the carrier, and the LHON patient and successfully differentiated into RGCs. These RGCs carried equivalent intracellular reactive oxygen species, but only LHON-patient iPSC-derived RGCs exhibited remarkable apoptosis. Next-generation sequencing and quantitative real-time PCR revealed the circRNA hsa_circ_0087207 as the most upregulated circRNA in LHON-patient iPSC-derived RGCs. Overexpression of hsa_circ_0087207 increased the apoptosis in carrier iPSC-derived RGCs, while knockdown of hsa_circ_0087207 attenuated the apoptosis in LHON-patient iPSC-derived RGCs. Predicted by bioinformatics approaches, hsa_circ_0087207 acts as the sponge of miR-665 to induce the expression of a variety of apoptosis-related genes in LHON patient iPSC-derived RGCs. Conclusions: Our data indicated that hsa_circ_0087207 upregulation distinguishes the disease phenotype manifestations between iPSC-derived RGCs generated from the LHON patient and carrier. Targeting the hsa_circ_0087207/miR-665 axis might hold therapeutic promises for the treatment of LHON.
2020-04-27 | miR-181a/b downregulation exerts a protective action on mitochondrial disease models.
Mitochondrial diseases (MDs) are a heterogeneous group of devastating and often fatal disorders due to defective oxidative phosphorylation. Despite the recent advances in mitochondrial medicine, effective therapies are still not available for these conditions. Here, we demonstrate that the microRNAs miR-181a and miR-181b (miR-181a/b) regulate key genes involved in mitochondrial biogenesis and function and that downregulation of these miRNAs enhances mitochondrial turnover in the retina through the coordinated activation of mitochondrial biogenesis and mitophagy. We thus tested the effect of miR-181a/b inactivation in different animal models of MDs, such as microphthalmia with linear skin lesions and Leber's hereditary optic neuropathy. We found that miR-181a/b downregulation strongly protects retinal neurons from cell death and significantly ameliorates the disease phenotype in all tested models. Altogether, our results demonstrate that miR-181a/b regulate mitochondrial homeostasis and that these miRNAs may be effective gene-independent therapeutic targets for MDs characterized by neuronal degeneration.
cell therapies
2026-03-02 | Mesenchymal stem cell mitochondrial transfer effectively protects Leber's Hereditary Optic Neuropathy (LHON) mutant cells from mitochondrial damage.
Leber's Hereditary Optic Neuropathy (LHON) is the most prevalent mitochondrial inherited disorder, primarily caused by primary mitochondrial mutations. Clinically, LHON is characterized by degeneration of optic nerves that leads to acute or subacute sudden or painless central vision loss. Currently no effective treatment has been established for LHON. Recent studies have highlighted the significance of intercellular mitochondrial transfer, which facilitates communication between cells and presents a novel therapeutic avenue. In this study, we investigated the formation of tunnelling nanotubes (TNTs) and the subsequent mitochondrial transfer between Bone Marrow Mesenchymal Stem Cells (BM-MSCs) and LHON ND4 mutant cells within the coculture system. Our findings demonstrated that mitochondrial transfer from BM-MSCs to LHON mutant cells via TNTs effectively rescued the mutant LHON cells by reducing apoptosis, restoring mitochondrial membrane potential and reducing reactive oxygen species (ROS) generation. These results provide compelling evidence of cell-cell communication between mesenchymal stem cells and LHON mutant cells, indicating a potential regenerative capacity through the reduction in mitochondrial mutation load. This study would help to implement further research in this area for the protective effect of mitochondria transfer and future cell-based treatment approaches for LHON.
2025-01-14 | Nanoengineered mitochondria enable ocular mitochondrial disease therapy via the replacement of dysfunctional mitochondria.
Leber's hereditary optic neuropathy (LHON) is an ocular mitochondrial disease that involves the impairment of mitochondrial complex I, which is an important contributor to blindness among young adults across the globe. However, the disorder has no available cures, since the approved drug idebenone for LHON in Europe relies on bypassing complex I defects rather than fixing them. Herein, PARKIN mRNA-loaded nanoparticle (mNP)-engineered mitochondria (mNP-Mito) were designed to replace dysfunctional mitochondria with the delivery of exogenous mitochondria, normalizing the function of complex I for treating LHON. The mNP-Mito facilitated the supplementation of healthy mitochondria containing functional complex I via mitochondrial transfer, along with the elimination of dysfunctional mitochondria with impaired complex I via an enhanced PARKIN-mediated mitophagy process. In a mouse model induced with a complex I inhibitor (rotenone, Rot), mNP-Mito enhanced the presence of healthy mitochondria and exhibited a sharp increase in complex I activity (76.5%) compared to the group exposed to Rot damage (29.5%), which greatly promoted the restoration of ATP generation and mitigation of ocular mitochondrial disease-related phenotypes. This study highlights the significance of nanoengineered mitochondria as a promising and feasible tool for the replacement of dysfunctional mitochondria and the repair of mitochondrial function in mitochondrial disease therapies.
2024-08-24 | Inhibition of angiogenesis by the secretome from iPSC-derived retinal ganglion cells with Leber's hereditary optic neuropathy-like phenotypes.
The blood supply in the retina ensures photoreceptor function and maintains regular vision. Leber's hereditary optic neuropathy (LHON), caused by the mitochondrial DNA mutations that deteriorate complex I activity, is characterized by progressive vision loss. Although some reports indicated retinal vasculature abnormalities as one of the comorbidities in LHON, the paracrine influence of LHON-affected retinal ganglion cells (RGCs) on vascular endothelial cell physiology remains unclear. To address this, we established an in vitro model of mitochondrial complex I deficiency using induced pluripotent stem cell-derived RGCs (iPSC-RGCs) treated with a mitochondrial complex I inhibitor rotenone (Rot) to recapitulate LHON pathologies. The secretomes from Rot-treated iPSC-RGCs (Rot-iPSC-RGCs) were collected, and their treatment effect on human umbilical vein endothelial cells (HUVECs) was studied. Rot induced LHON-like characteristics in iPSC-RGCs, including decreased mitochondrial complex I activity and membrane potential, and increased mitochondrial reactive oxygen species (ROS) and apoptosis, leading to mitochondrial dysfunction. When HUVECs were exposed to conditioned media (CM) from Rot-iPSC-RGCs, the angiogenesis of HUVECs was suppressed compared to those treated with CM from control iPSC-RGCs (Ctrl-iPSC-RGCs). Angiogenesis-related proteins were altered in the secretomes from Rot-iPSC-RGC-derived CM, particularly angiopoietin, MMP-9, uPA, collagen XVIII, and VEGF were reduced. Notably, GeneMANIA analysis indicated that VEGFA emerged as the pivotal angiogenesis-related protein among the identified proteins secreted by health iPSC-RGCs but reduced in the secretomes from Rot-iPSC-RGCs. Quantitative real-time PCR and western blots confirmed the reduction of VEGFA at both transcription and translation levels, respectively. Our study reveals that Rot-iPSC-RGCs establish a microenvironment to diminish the angiogenic potential of vascular cells nearby, shedding light on the paracrine regulation of LHON-affected RGCs on retinal vasculature.
2024-08-13 | MSC-mediated mitochondrial transfer restores mitochondrial DNA and function in neural progenitor cells of Leber's hereditary optic neuropathy.
Leber's hereditary optic neuropathy (LHON) is a debilitating mitochondrial disease associated with mutations in mitochondrial DNA (mtDNA). Unfortunately, the available treatment options for LHON patients are limited due to challenges in mitochondrial replacement. In our study, we reprogramming LHON urine cells into induced pluripotent stem cells (iPSCs) and differentiating them into neural progenitor cells (NPCs) and neurons for disease modeling. Our research revealed that LHON neurons exhibited significantly higher levels of mtDNA mutations and reduced mitochondrial function, confirming the disease phenotype. However, through co-culturing LHON iPSC-derived NPCs with mesenchymal stem cells (MSCs), we observed a remarkable rescue of mutant mtDNA and a significant improvement in mitochondrial metabolic function in LHON neurons. These findings suggest that co-culturing with MSCs can enhance mitochondrial function in LHON NPCs, even after their differentiation into neurons. This discovery holds promise as a potential therapeutic strategy for LHON patients.
2024-01-22 | Hereditary Optic Neuropathies: A Systematic Review on the Interplay between Biomaterials and Induced Pluripotent Stem Cells.
Hereditary optic neuropathies (HONs) such as dominant optic atrophy (DOA) and Leber Hereditary Optic Neuropathy (LHON) are mitochondrial diseases characterized by a degenerative loss of retinal ganglion cells (RGCs) and are a cause of blindness worldwide. To date, there are only limited disease-modifying treatments for these disorders. The discovery of induced pluripotent stem cell (iPSC) technology has opened several promising opportunities in the field of HON research and the search for therapeutic approaches. This systematic review is focused on the two most frequent HONs (LHON and DOA) and on the recent studies related to the application of human iPSC technology in combination with biomaterials technology for their potential use in the development of RGC replacement therapies with the final aim of the improvement or even the restoration of the vision of HON patients. To this purpose, the combination of natural and synthetic biomaterials modified with peptides, neurotrophic factors, and other low- to medium-molecular weight compounds, mimicking the ocular extracellular matrices, with human iPSC or iPSC-derived cell retinal progenitors holds enormous potential to be exploited in the near future for the generation of transplantable RGC populations.
other
2024-08-02 | Co-occurrence of glial fibrillary acidic protein astrocytopathy in a patient with Leber's hereditary optic neuropathy due to DNAJC30 mutations.
Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by visual loss, and rarely associated with extraocular manifestations including multiple sclerosis-like lesions. The association of LHON and neuromyelitis optica spectrum disorders has rarely been reported. Here is reported a case of glial fibrillary acidic protein astrocytopathy presenting with area postrema syndrome in a patient with previously diagnosed recessive LHON due to mutations in the nuclear gene DNAJC30. This case emphasizes the necessity of extensive investigations for other treatable conditions in patients with LHON and otherwise unexplained extraocular involvement and the possibility that also visual symptoms can respond to immune therapy.
1992-01-01 | OCCURRENCE OF A MULTIPLE SCLEROSIS-LIKE ILLNESS IN WOMEN WHO HAVE A LEBER'S HEREDITARY OPTIC NEUROPATHY MITOCHONDRIAL DNA MUTATION
Eight women are described who presented with bilateral, usually sequential, optic neuropathy, six of whom later developed a neurological syndrome indistinguishable from multiple sclerosis (MS) Magnetic resonance imaging, performed in five of the patients with an MS-like illness and in the two others with optic neuropathy alone, showed widespread white matter lesions as seen in MS All of these women had matrilineal relatives with Leber's hereditary optic neuropathy, although this was not always apparent at presentation, and the most common mitochondrial DNA mutation associated with this disorder was detected in each of the women and their affected relatives On the basis of observations made in these patients, the clinical features of Leber's hereditary optic neuropathy in males, and evidence for mitochondrially encoded peptides involved in the immune response in rodents, we propose that optic nerve damage in this disease could be immunologically mediated and that mitochondrial genes may contribute to susceptibility to MS.
small molecules
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.
2026-07-27 | 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.
2026-07-07 | When LHON Mimics Demyelination: Area Postrema Syndrome in Biallelic DNAJC30 Variants
Introduction: Biallelic pathogenic variants in DNAJC30 cause an autosomal recessive form of Leber hereditary optic neuropathy (LHONAR1), traditionally considered a mitochondrially transmitted disorder. The phenotypic spectrum of diseases linked to DNAJC30 includes isolated optic neuropathy, Leigh syndrome spectrum (LSS), and atypical LHON-plus. Case description: Here, we report a 13-year-old boy presenting symptoms of area postrema syndrome (APS), with recurrent vomiting, vertigo, nystagmus, and subacute visual deterioration with central scotoma. Ophthalmological examination revealed bilateral papilledema with telangiectatic vessels, while visual evoked potentials demonstrated severe bilateral optic pathway dysfunction. Brain magnetic resonance imaging (MRI) showed T2/FLAIR hyperintense lesions involving the area postrema and enhancement of the optic nerves, strongly suggesting seronegative neuromyelitis optica spectrum disorder (NMOSD). Extensive immunological and cerebrospinal fluid studies, including anti-aquaporin-4 (AQP4) and anti-MOG antibodies, were negative. High-dose corticosteroids and intravenous immunoglobulins resulted in only transient and incomplete improvement, followed by further visual decline. Additionally, laboratory tests detected elevated lactate plasma levels. Hence, whole-exome sequencing was performed, which identified a homozygous pathogenic DNAJC30 c.152A>G, p.(Tyr51Cys) variant, associated with LHONAR1. After initiation of idebenone therapy, the patient showed significant improvement in visual function, normalization of lactate levels, and complete resolution of the brainstem lesions on follow-up MRI. Conclusions: This case further expands the neuro-ophthalmic spectrum associated with DNAJC30 variants and suggests that DNAJC30-related disease may closely mimic seronegative NMOSD. We highlight that early genetic diagnosis is essential, as recognition of this mitochondrial etiology enables targeted therapy and may substantially improve clinical outcomes.
2026-06-27 | Clinical development in primary mitochondrial diseases at a translational inflection point: Lessons, mechanisms, and emerging therapeutic strategies.
Clinical development for primary mitochondrial diseases (PMDs) has spanned more than two decades, yet therapeutic success remains limited. In this Review, we provide a comprehensive, pharmacology-focused analysis of the PMD clinical trial landscape and identify key mechanistic and translational determinants underlying recent progress. A systematic survey of ClinicalTrials.gov covering January 2010 to April 2026 identified 159 registered studies across PMD subtypes after deduplication, including 110 interventional trials. Progress has been constrained by marked genetic and phenotypic heterogeneity, small and geographically dispersed patient populations, and the lack of validated pharmacodynamic and disease-specific endpoints. Consequently, several well-designed late-stage trials have yielded negative or inconclusive outcomes, and regulatory approvals have historically been scarce. Recent advances, however, indicate a shift in trajectory. Four therapies have achieved regulatory authorization, including idebenone for Leber hereditary optic neuropathy, taurine for MELAS, and recent FDA approvals of doxecitine and doxribtimine (Kygevvi) for thymidine kinase 2 deficiency and elamipretide (FORZINITY) for Barth syndrome. These successes share a convergent translational framework integrating mechanism-based pharmacology, genotype-driven patient selection, and biologically aligned endpoints. Clinical activity has also accelerated, with approximately half of PMD interventional trials initiated since 2020 and 50 studies currently active or recruiting. Emerging strategies include NAD⁺ augmentation, soluble guanylate cyclase stimulation, mTOR modulation, gene therapies, and heteroplasmy-targeting approaches. Collectively, these advances mark an emerging inflection point and suggest a path toward greater regulatory success in the coming decade.
gene therapies
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.
2026-07-31 | 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.
2026-05-14 | Gene Therapy for Leber Hereditary Optic Neuropathy (LHON): A Systematic Review and Meta-Analysis.
LHON is a rare mitochondrial disease causing bilateral vision loss, most commonly due to the m.11778G>A mutation. rAAV2/2-ND4 gene therapy is a potential disease-modifying treatment. Systematic review and meta-analysis of three RCTs (RESCUE, REVERSE, REFLECT) including 175 patients. Gene therapy significantly improved best-corrected visual acuity but did not significantly increase responder rates. Adverse events were mostly mild ocular inflammation, with no treatment-related mortality. rAAV2/2-ND4 is a moderately effective and safe treatment for LHON, though long-term outcomes and predictors of response remain unclear.
2026-04-16 | LEBER'S HEREDITARY OPTIC NEUROPATHY (LHON): A GLOBAL COMPARISON WITH SPECIAL EMPHASIS ON INDIA
Leber’s hereditary optic neuropathy (LHON) is a rare mitochondrial genetic disorder, which is characterized by acute to subacute painless loss of central vision in young adult males. It is caused by a point mutation of mitochondrial DNA, which includes m. 11778G>A, m.3460G>A, m. and m. 14484T>C, resulting in retinal ganglion cell loss due to optic neuropathy. The prevalence of LHON worldwide is considerably variable due to genetic predisposition, geographical factors, and technical factors. In India, LHON is believed to be underdiagnosed and underreported compared to Western and East Asian nations. Also, Limited Availability of physician awareness in LHON can lead to a delay in diagnosis. Data collected in India shows a relatively high prevalence of sporadic cases and different mutations, of which m. 11778G>a is the predominant mutation. Environmental factors such as alcohol and cigarette use, nutritional deficiencies, and toxic exposures could also affect LHON and impact affected individuals in India. By contrast, the prevalence of better epidemiological data is observed in Japan, China, Europe, and the United States owing to the presence of genetic screening programs and patient registries. Japan has a relatively higher prevalence of m.11778G>A mutations, and European cohorts have a better rate of visual recovery owing to early intervention and treatment with odobenine and novel gene therapies based on adeno-associated virus vectors. In general, though LOHN is a worldwide phenomenon, there are considerable variations between Indian and international cases recording diagnosis, handling, and advancement in research. Enhancement in genetic lab facilities, awareness among doctors, and availability of new treatment are needed for improving the present status of LOHN in India.
2026-03-18 | Visual Loss from Leber's Optic Neuropathy Presenting in a 76-Year-Old Man with the 14484 Mutations.
Leber's Hereditary Optic Neuropathy (LHON) is an important hereditary optic neuropathy that typically causes bilateral visual loss, predominantly in male patients. While it usually manifests in young adults, it can uncommonly present in older individuals without a family history, potentially leading to diagnostic confusion. The mechanisms underlying why some individuals with these mutations develop optic neuropathy while others remain asymptomatic are still under investigation. Factors such as heteroplasmy, epigenetic modifications, and environmental triggers, including alcohol consumption, are thought to contribute. However, the exact triggers that convert carriers into symptomatic individuals remain poorly understood, with cigarette smoking and alcohol intake being potential contributors. The purpose of this paper is to describe a 76-year-old patient who experienced, painless bilateral visual loss progressing over 4 weeks. Despite extensive evaluation, including imaging, blood tests, and genetic testing, a mitochondrial mutation (T14484C) associated with LHON was identified. Although LHON is rare, especially in the elderly, and usually presents in younger males, this case highlights the need for clinicians to consider LHON as a potential diagnosis in older patients presenting with unexplained visual loss.
oligonucleotides
2025-11-02 | Mitochondrial genome microhomology-mediated editing by donor DNA delivery into mitochondria in human cells
Summary Mutations in the mitochondrial DNA (mtDNA) are associated with severe human diseases, lacking efficient therapies. Direct correction of mtDNA mutations may offer a cure for such diseases. We propose a novel strategy based on double-stranded DNA (dsDNA) oligonucleotide delivery into mitochondria and intrinsic microhomology-mediated end joining (MMEJ) for mtDNA editing. This strategy enables introduction of multiple predefined nucleotide changes in mtDNA. For this, the presence of MMEJ activity in the human mitochondrial lysates was confirmed. 49 bp DNA oligonucleotide duplexes, fused to an RNA hairpin previously identified as a mitochondrial import signal, were delivered into the mitochondria of cultured human cells. Delivery of these donor dsDNA molecules, homological to an ND4 site of mtDNA and bearing designed nucleotide changes, led to a low but statistically significant introduction of the designed nucleotide changes into mtDNA. Donor dsDNA delivery combined with the CRISPR/mito-AsCas12a system also resulted in a statistically significant number of an expected concomitant change of five nucleotides distributed across a 16-nucleotide ND4 site of the mitochondrial genome. The proposed strategy may become an efficient mtDNA editing tool suitable for the correction of near-homoplasmic mutations such as Leber’s Hereditary Optic Neuropathy (LHON)-associated mutations in the ND4 gene of mtDNA.
2024-03-06 | Dysregulation of the circRNA_0087207/miR-548c-3p/PLSR1-TGFB2 axis in Leber hereditary optic neuropathy in vitro.
Leber hereditary optic neuropathy (LHON) is mainly the degeneration of retinal ganglion cells (RGCs) associated with high apoptosis and reactive oxygen species (ROS) levels, which is accepted to be caused by the mutations in the subunits of complex I of the mitochondrial electron transport chain. The treatment is still infant while efforts of correcting genes or using antioxidants do not bring good and consistent results. Unaffected carrier carries LHON mutation but shows normal phenotype, suggesting that the disease's pathogenesis is complex, in which secondary factors exist and cooperate with the primary complex I dysfunction. Using LHON patient-specific induced pluripotent stem cells (iPSCs) as the in vitro disease model, we previously demonstrated that circRNA_0087207 had the most significantly higher expression level in the LHON patient-iPSC-derived RGCs compared with the unaffected carrier-iPSC-derived RGCs. To elaborate the underlying pathologies regulated by circRNA_008720 mechanistically, bioinformatics analysis was conducted and elucidated that circRNA_0087207 could act as a sponge of miR-548c-3p and modulate PLSCR1/TGFB2 levels in ND4 mutation-carrying LHON patient-iPSC-derived RGCs. Using LHON iPSC-derived RGCs as the disease-based platform, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis on targeted mRNA of miR-548c-3p showed the connection with apoptosis, suggesting downregulation of miR548c-3p contributes to the apoptosis of LHON patient RGCs. We showed that the downregulation of miR548c-3p plays a critical role in modulating cellular dysfunction and the apoptotic program of RGCs in LHON.
2023-08-01 | Mitochondrial transport of catalytic RNAs and targeting of the organellar transcriptome in human cells
Abstract Mutations in the small genome present in mitochondria often result in severe pathologies. Different genetic strategies have been explored, aiming to rescue such mutations. A number of these strategies were based on the capacity of human mitochondria to import RNAs from the cytosol and designed to repress the replication of the mutated genomes or to provide the organelles with wild-type versions of mutant transcripts. However, the mutant RNAs present in mitochondria turned out to be an obstacle to therapy and little attention has been devoted so far to their elimination. Here, we present the development of a strategy to knockdown mitochondrial RNAs in human cells using the transfer RNA-like structure of Brome mosaic virus or Tobacco mosaic virus as a shuttle to drive trans-cleaving ribozymes into the organelles in human cell lines. We obtained a specific knockdown of the targeted mitochondrial ATP6 mRNA, followed by a deep drop in ATP6 protein and a functional impairment of the oxidative phosphorylation chain. Our strategy provides a powerful approach to eliminate mutant organellar transcripts and to analyse the control and communication of the human organellar genetic system.
2022-03-28 | Retinal Circular RNA hsa_circ_0087207 Expression Promotes Apoptotic Cell Death in Induced Pluripotent Stem Cell-Derived Leber’s Hereditary Optic Neuropathy-like Models
Backgrounds: Leber's hereditary optic neuropathy (LHON) is known as an inherited retinal disorder characterized by the bilateral central vision loss and degeneration of retinal ganglion cells (RGCs). Unaffected LHON carriers are generally asymptomatic, suggesting that certain factors may contribute to the disease manifestations between carriers and patients who carry the same mutated genotypes. Methods: We first aimed to establish the iPSC-differentiated RGCs from the normal healthy subject, the carrier, and the LHON patient and then compared the differential expression profile of circular RNAs (CircRNAs) among RGCs from these donors in vitro. We further overexpressed or knocked down the most upregulated circRNA to examine whether this circRNA contributes to the distinct phenotypic manifestations between the carrier- and patient-derived RGCs. Results: iPSCs were generated from the peripheral blood cells from the healthy subject, the carrier, and the LHON patient and successfully differentiated into RGCs. These RGCs carried equivalent intracellular reactive oxygen species, but only LHON-patient iPSC-derived RGCs exhibited remarkable apoptosis. Next-generation sequencing and quantitative real-time PCR revealed the circRNA hsa_circ_0087207 as the most upregulated circRNA in LHON-patient iPSC-derived RGCs. Overexpression of hsa_circ_0087207 increased the apoptosis in carrier iPSC-derived RGCs, while knockdown of hsa_circ_0087207 attenuated the apoptosis in LHON-patient iPSC-derived RGCs. Predicted by bioinformatics approaches, hsa_circ_0087207 acts as the sponge of miR-665 to induce the expression of a variety of apoptosis-related genes in LHON patient iPSC-derived RGCs. Conclusions: Our data indicated that hsa_circ_0087207 upregulation distinguishes the disease phenotype manifestations between iPSC-derived RGCs generated from the LHON patient and carrier. Targeting the hsa_circ_0087207/miR-665 axis might hold therapeutic promises for the treatment of LHON.
2020-04-27 | miR-181a/b downregulation exerts a protective action on mitochondrial disease models.
Mitochondrial diseases (MDs) are a heterogeneous group of devastating and often fatal disorders due to defective oxidative phosphorylation. Despite the recent advances in mitochondrial medicine, effective therapies are still not available for these conditions. Here, we demonstrate that the microRNAs miR-181a and miR-181b (miR-181a/b) regulate key genes involved in mitochondrial biogenesis and function and that downregulation of these miRNAs enhances mitochondrial turnover in the retina through the coordinated activation of mitochondrial biogenesis and mitophagy. We thus tested the effect of miR-181a/b inactivation in different animal models of MDs, such as microphthalmia with linear skin lesions and Leber's hereditary optic neuropathy. We found that miR-181a/b downregulation strongly protects retinal neurons from cell death and significantly ameliorates the disease phenotype in all tested models. Altogether, our results demonstrate that miR-181a/b regulate mitochondrial homeostasis and that these miRNAs may be effective gene-independent therapeutic targets for MDs characterized by neuronal degeneration.
cell therapies
2026-03-02 | Mesenchymal stem cell mitochondrial transfer effectively protects Leber's Hereditary Optic Neuropathy (LHON) mutant cells from mitochondrial damage.
Leber's Hereditary Optic Neuropathy (LHON) is the most prevalent mitochondrial inherited disorder, primarily caused by primary mitochondrial mutations. Clinically, LHON is characterized by degeneration of optic nerves that leads to acute or subacute sudden or painless central vision loss. Currently no effective treatment has been established for LHON. Recent studies have highlighted the significance of intercellular mitochondrial transfer, which facilitates communication between cells and presents a novel therapeutic avenue. In this study, we investigated the formation of tunnelling nanotubes (TNTs) and the subsequent mitochondrial transfer between Bone Marrow Mesenchymal Stem Cells (BM-MSCs) and LHON ND4 mutant cells within the coculture system. Our findings demonstrated that mitochondrial transfer from BM-MSCs to LHON mutant cells via TNTs effectively rescued the mutant LHON cells by reducing apoptosis, restoring mitochondrial membrane potential and reducing reactive oxygen species (ROS) generation. These results provide compelling evidence of cell-cell communication between mesenchymal stem cells and LHON mutant cells, indicating a potential regenerative capacity through the reduction in mitochondrial mutation load. This study would help to implement further research in this area for the protective effect of mitochondria transfer and future cell-based treatment approaches for LHON.
2025-01-14 | Nanoengineered mitochondria enable ocular mitochondrial disease therapy via the replacement of dysfunctional mitochondria.
Leber's hereditary optic neuropathy (LHON) is an ocular mitochondrial disease that involves the impairment of mitochondrial complex I, which is an important contributor to blindness among young adults across the globe. However, the disorder has no available cures, since the approved drug idebenone for LHON in Europe relies on bypassing complex I defects rather than fixing them. Herein, PARKIN mRNA-loaded nanoparticle (mNP)-engineered mitochondria (mNP-Mito) were designed to replace dysfunctional mitochondria with the delivery of exogenous mitochondria, normalizing the function of complex I for treating LHON. The mNP-Mito facilitated the supplementation of healthy mitochondria containing functional complex I via mitochondrial transfer, along with the elimination of dysfunctional mitochondria with impaired complex I via an enhanced PARKIN-mediated mitophagy process. In a mouse model induced with a complex I inhibitor (rotenone, Rot), mNP-Mito enhanced the presence of healthy mitochondria and exhibited a sharp increase in complex I activity (76.5%) compared to the group exposed to Rot damage (29.5%), which greatly promoted the restoration of ATP generation and mitigation of ocular mitochondrial disease-related phenotypes. This study highlights the significance of nanoengineered mitochondria as a promising and feasible tool for the replacement of dysfunctional mitochondria and the repair of mitochondrial function in mitochondrial disease therapies.
2024-08-24 | Inhibition of angiogenesis by the secretome from iPSC-derived retinal ganglion cells with Leber's hereditary optic neuropathy-like phenotypes.
The blood supply in the retina ensures photoreceptor function and maintains regular vision. Leber's hereditary optic neuropathy (LHON), caused by the mitochondrial DNA mutations that deteriorate complex I activity, is characterized by progressive vision loss. Although some reports indicated retinal vasculature abnormalities as one of the comorbidities in LHON, the paracrine influence of LHON-affected retinal ganglion cells (RGCs) on vascular endothelial cell physiology remains unclear. To address this, we established an in vitro model of mitochondrial complex I deficiency using induced pluripotent stem cell-derived RGCs (iPSC-RGCs) treated with a mitochondrial complex I inhibitor rotenone (Rot) to recapitulate LHON pathologies. The secretomes from Rot-treated iPSC-RGCs (Rot-iPSC-RGCs) were collected, and their treatment effect on human umbilical vein endothelial cells (HUVECs) was studied. Rot induced LHON-like characteristics in iPSC-RGCs, including decreased mitochondrial complex I activity and membrane potential, and increased mitochondrial reactive oxygen species (ROS) and apoptosis, leading to mitochondrial dysfunction. When HUVECs were exposed to conditioned media (CM) from Rot-iPSC-RGCs, the angiogenesis of HUVECs was suppressed compared to those treated with CM from control iPSC-RGCs (Ctrl-iPSC-RGCs). Angiogenesis-related proteins were altered in the secretomes from Rot-iPSC-RGC-derived CM, particularly angiopoietin, MMP-9, uPA, collagen XVIII, and VEGF were reduced. Notably, GeneMANIA analysis indicated that VEGFA emerged as the pivotal angiogenesis-related protein among the identified proteins secreted by health iPSC-RGCs but reduced in the secretomes from Rot-iPSC-RGCs. Quantitative real-time PCR and western blots confirmed the reduction of VEGFA at both transcription and translation levels, respectively. Our study reveals that Rot-iPSC-RGCs establish a microenvironment to diminish the angiogenic potential of vascular cells nearby, shedding light on the paracrine regulation of LHON-affected RGCs on retinal vasculature.
2024-08-13 | MSC-mediated mitochondrial transfer restores mitochondrial DNA and function in neural progenitor cells of Leber's hereditary optic neuropathy.
Leber's hereditary optic neuropathy (LHON) is a debilitating mitochondrial disease associated with mutations in mitochondrial DNA (mtDNA). Unfortunately, the available treatment options for LHON patients are limited due to challenges in mitochondrial replacement. In our study, we reprogramming LHON urine cells into induced pluripotent stem cells (iPSCs) and differentiating them into neural progenitor cells (NPCs) and neurons for disease modeling. Our research revealed that LHON neurons exhibited significantly higher levels of mtDNA mutations and reduced mitochondrial function, confirming the disease phenotype. However, through co-culturing LHON iPSC-derived NPCs with mesenchymal stem cells (MSCs), we observed a remarkable rescue of mutant mtDNA and a significant improvement in mitochondrial metabolic function in LHON neurons. These findings suggest that co-culturing with MSCs can enhance mitochondrial function in LHON NPCs, even after their differentiation into neurons. This discovery holds promise as a potential therapeutic strategy for LHON patients.
2024-01-22 | Hereditary Optic Neuropathies: A Systematic Review on the Interplay between Biomaterials and Induced Pluripotent Stem Cells.
Hereditary optic neuropathies (HONs) such as dominant optic atrophy (DOA) and Leber Hereditary Optic Neuropathy (LHON) are mitochondrial diseases characterized by a degenerative loss of retinal ganglion cells (RGCs) and are a cause of blindness worldwide. To date, there are only limited disease-modifying treatments for these disorders. The discovery of induced pluripotent stem cell (iPSC) technology has opened several promising opportunities in the field of HON research and the search for therapeutic approaches. This systematic review is focused on the two most frequent HONs (LHON and DOA) and on the recent studies related to the application of human iPSC technology in combination with biomaterials technology for their potential use in the development of RGC replacement therapies with the final aim of the improvement or even the restoration of the vision of HON patients. To this purpose, the combination of natural and synthetic biomaterials modified with peptides, neurotrophic factors, and other low- to medium-molecular weight compounds, mimicking the ocular extracellular matrices, with human iPSC or iPSC-derived cell retinal progenitors holds enormous potential to be exploited in the near future for the generation of transplantable RGC populations.
other
2024-08-02 | Co-occurrence of glial fibrillary acidic protein astrocytopathy in a patient with Leber's hereditary optic neuropathy due to DNAJC30 mutations.
Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by visual loss, and rarely associated with extraocular manifestations including multiple sclerosis-like lesions. The association of LHON and neuromyelitis optica spectrum disorders has rarely been reported. Here is reported a case of glial fibrillary acidic protein astrocytopathy presenting with area postrema syndrome in a patient with previously diagnosed recessive LHON due to mutations in the nuclear gene DNAJC30. This case emphasizes the necessity of extensive investigations for other treatable conditions in patients with LHON and otherwise unexplained extraocular involvement and the possibility that also visual symptoms can respond to immune therapy.
1992-01-01 | OCCURRENCE OF A MULTIPLE SCLEROSIS-LIKE ILLNESS IN WOMEN WHO HAVE A LEBER'S HEREDITARY OPTIC NEUROPATHY MITOCHONDRIAL DNA MUTATION
Eight women are described who presented with bilateral, usually sequential, optic neuropathy, six of whom later developed a neurological syndrome indistinguishable from multiple sclerosis (MS) Magnetic resonance imaging, performed in five of the patients with an MS-like illness and in the two others with optic neuropathy alone, showed widespread white matter lesions as seen in MS All of these women had matrilineal relatives with Leber's hereditary optic neuropathy, although this was not always apparent at presentation, and the most common mitochondrial DNA mutation associated with this disorder was detected in each of the women and their affected relatives On the basis of observations made in these patients, the clinical features of Leber's hereditary optic neuropathy in males, and evidence for mitochondrially encoded peptides involved in the immune response in rodents, we propose that optic nerve damage in this disease could be immunologically mediated and that mitochondrial genes may contribute to susceptibility to MS.
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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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