Reviews of LHON treatment prospects and concepts
Listed in references below are important reviews of the research and treatment prospects in Leber Hereditary Optic Neuropathy [LHON] with editorial comments. NOTE: None of these are accepted treatments for LHON. Always discuss treatment with your personal health professional. To support more research in this important direction for saving sight and likely flow on effects for general health, please donate.
Glia
Nervous system glial cells support neurons. Studies on their function in the nervous system may lead to treatment prospects in various neurodegenerative diseases. IFOND is supporting such studies.
Correale, J.2026. “Glial Plasticity and Dysfunction: Mechanistic Insights and Therapeutic Opportunities in Neurodegeneration.” Journal of Neurochemistry 170, no. 4: e70414. https://doi.org/10.1111/jnc.70414. https://onlinelibrary.wiley.com/doi/10.1111/jnc.70414
Hosseini S, Thakur P, Cedeno DL, Fereidoni M, Elahdadi Salmani M. Editorial: Glial cells in health and disease: impacts on neural circuits and plasticity. Front Cell Neurosci. 2025 Feb 20;19:1569725. doi: 10.3389/fncel.2025.1569725. PMID: 40051677; PMCID: PMC11882510. https://pmc.ncbi.nlm.nih.gov/articles/PMC11882510/
Wang Y, Feng B, Hong R, Qiu D, Zhao J, Zhao L. Glial lactate metabolism and transport in Alzheimer's disease. Front Aging Neurosci. 2026 Mar 18;18:1731089. doi: 10.3389/fnagi.2026.1731089. PMID: 41930368; PMCID: PMC13038885. PMCID: PMC13038885
Metformin
Below see a case report by some of our scientific board members of possible improvement of a post menopausal LHON case associated with use of metformin for treatment of her type 2 diabetes mellitus. The discussion suggests further exploration of metformin treatment in disease models is indicated. A review referenced below of mitochondrial dysfunction including LHON mtDNA alleles in insulin resistance and polycystic ovarian disease may be relevant.
Elmaseh SA, Gauthier DA, Golmohammadi M, Pargalava N, Carelli V and Sadun AA (2025) Metformin may alter the course of Leber’s hereditary optic neuropathy: a case report. Front. Med. 12:1609941. doi: 10.3389/fmed.2025.1609941 https://doi.org/10.3389/fmed.2025.1609941
Tharayil SP, Shukla P. Connecting the Dots: Mitochondrial Dysfunction, PCOS, and Insulin Resistance-Insights and Therapeutic Advances. International Journal of Molecular Sciences. 2025 Jun;26(13):6233. DOI: 10.3390/ijms26136233. PMID: 40650016; PMCID: PMC12249811. https://doi.org/10.3390/ijms26136233
Epigenetics
Expression of nuclear DNA genes is partially dependant on factors external to the encoded gene information. These epigenetic factors are postulated to play a role in the variable penetrance of LHON. Understanding the mechanisms in detail may lead to prevention and therapy. A recent study exploring epigenetic nuclear factors influencing mithochondrial protein function involved in LHON is referenced below.
Nair, A.P., Selvakumar, A., Gopalarethinam, J. et al. Epigenetic regulation of the nuclear genome associated with mitochondrial dysfunction in Leber’s hereditary optic neuropathy (LHON). Hum Genome Var 11, 6 (2024). https://doi.org/10.1038/s41439-023-00258-5
Melatonin
Melatonin, a mitochondrial product, is a very powerful ampiphilic [water and lipid soluble] cascading scavenger of multiple reactive oxidant species. It is produced in the pineal gland where it regulates the sleep cycle with feedback from intrinsically photosensitive melanopsin retinal ganglion cells[ipRGCs] to the suprachiasmatic nucleus. [Incidently, melanopsin is a G-protein coupled receptor, also found in high amounts in fat cells. IpRGCs are relatively spared in LHON. Why? One clue may be in the fact that photoreceptor nanotubes mediate the exchange of intracellular material. ] Melatonin is made in the eye in the photoreceptors and in the ciliary body. It is also made in massive amounts in the gastrointestinal tract and skin with appropriate stimulation, tryptophan intake and near infrared light respectively. In the eye exist G-protein coupled melatonin receptors types MT1, MT2, and, only in amphibia and birds, MT3. Melatonin receptors are found in ciliary body, iris and retina. Melatonin has a circadian regulatory function in intraocular pressure. Melatonin has antioxidant and anti autophagy effects as well as a role in tunnelling nanotubes, important among other things for mitochondrial transport. It is used experimentally in models of optic nerve trauma, inflammation, glaucoma and retinal disease. A March 2025 review of glaucoma therapies revisits the potential role of melatonin and again points out lack of human studies so far.
Melatonin is being studied as a major part of the mechanism in and a therapy for neuronal recovery. Luchetti F, Carloni S, Nasoni MG, Reiter RJ, Balduini W. Tunneling nanotubes and mesenchymal stem cells: New insights into the role of melatonin in neuronal recovery. J Pineal Res. 2022 Aug;73(1):e12800. doi: 10.1111/jpi.12800. Epub 2022 Apr 22. PMID: 35419879; PMCID: PMC9540876.
Vitamin A
Our friend Douglas Wallace, the discoverer of the LHON mitochondrial mutation, coauthored a study on Vitamin A supplementation in a rodent LHON model. Caveat this does not directly translate to humans, and the relative Vitamin A dose used was human toxic, but a very interesting step in understanding and exposing a potential LHON therapy.
Polymorphic genetic variants
The search continues for nuclear genetic factors which may influence the puzzling variable penetrance of LHON. Recently recognised as well as mitochondrial LHON [mLHON] is autosomal recessive LHON [arLHON] [see OMIM#619382.] This adds to the continuum of genetic variants like autosomal recessive optic atrophy[aOA] affecting similar energy pathways and causing similar syndromes. The 2025 study from Arany et al tantalises with suggestions that there are indeed autosomal gene variants influencing penetrance in mitochondrial LHON. The strength of the findings were limited by small sample size. The researchers used European registries of LHON. This again demonstrates the importance of registries in the study of LHON.
Coauthored by some of the IFOND Scientific Advisory Board, a study published in 2024 relates failures of ibedenone therapy to polymorphic genetic variants causing lower levels of cytosolic NAD(P)H oxidoreductase I (NQO1). Ibedenone facilitates mitochondrial electron flux through directly shuttling electrons to respiratory complex III, bypassing complex I affected in LHON. NQO1 reduces idebenone from its oxidised state, allowing it to work as intended and preventing its potentially harmful oxidising action. This finding may guide better selection of patients for treatment, studies which elucidate other clinical strategies compensating for this, and ideally, preventative interventions in LHON. It also may help to explain the mysterious penetrance problem in LHON: Why do some carriers get LHON and others do not?
Arany, E.S., Olimpio, C., Paramonov, I. et al. Modifier variants in metabolic pathways are associated with an increased penetrance of Leber’s Hereditary Optic Neuropathy. Eur J Hum Genet (2025). https://doi.org/10.1038/s41431-025-01860-7
Gene Therapy
Lead by our scientific board member, Patrick Yu-Wai-Man, world leading Leber Hereditary Optic Neuropathy (LHON) researchers in the LHON Study Group including a majority of our scientific board have published a review [open access] of outcomes five years post single eye intraocular gene therapy in LHON. The Best Corrected Visual Acuity results suggest a lasting clinically significant therapeutic effect in both eyes in 41 of 62 participants (66%). Quality of life and adverse events were the other end points of the study. Both were favourable. An analysis and critique of the study is found in the accompanying editorial [paywalled].
Programmed cell death
Understanding the mechanics of programmed cell death relevant to optic nerve disease is a focus of current research into potential treatments and prevention:
Yang et al in 2024 comprehensively and thoughtfully review mitochondria and oxidative stress in retinal ganglion cells. Yang TH, Kang EY, Lin PH, Yu BB, Wang JH, Chen V, Wang NK. Mitochondria in Retinal Ganglion Cells: Unraveling the Metabolic Nexus and Oxidative Stress. Int J Mol Sci. 2024 Aug 7;25(16):8626. doi: 10.3390/ijms25168626. PMID: 39201313; PMCID: PMC11354650.
This Russian study found LHON fibroblasts prone to ferroptosis. Whereas most LHON literature discusses the intrinsic pathway of apoptosis as the mechanism of programmed cell death in LHON. Lyamzaev KG, Panteleeva AA, Simonyan RA, Avetisyan AV, Chernyak BV. Mitochondrial Lipid Peroxidation Is Responsible for Ferroptosis. Cells. 2023 Feb 13;12(4):611. doi: 10.3390/cells12040611. PMID: 36831278; PMCID: PMC9954536.
Photobiomodulation
A review was published in 2024 on photobiomodulation in various eye diseases. In 2021 Beirne, Freeman, Rozanowska, and Votruba [IFOND Scientific Board member] published a study showing effectiveness of red light stimulation on a mouse model of autosomal dominant optic atrophy. Therapeutic studies in LHON unfortunately have been delayed after a initial start in 2004. The mechanism of the effects of photobiomodulation are yet only partially explained. This area deserves further research with respect to LHON.
Computer simulation models
In 2023 Fuller , et al [including our scientific board member, Dr Alfredo Sadun] created a computer model of the LHON mutation 3460 G>A. The study found valuable detail in understanding the mechanism slowing electron transfer in Complex I and resulting in increased damaging reactive oxygen species in the retinal ganglion cell neuron : Fuller JT 3rd, Barnes S, Sadun LA, Ajmera P, Alexandrova AN, Sadun AA. Coenzyme Q10 trapping in mitochondrial complex I underlies Leber hereditary optic neuropathy. Proc Natl Acad Sci U S A. 2023 Sep 26;120(39):e2304884120. doi: 10.1073/pnas.2304884120. Epub 2023 Sep 21. PMID: 37733737; PMCID: PMC10523484.
Overviews
In 2022 Spiegel and Sadun offered an Overview of Current and Future Treatment Strategies in Lebers Hereditary Opic Neuropathy. They outline their current understanding of the disease, therapies, past, current and potential and suggest research paths.
The 2020 review by Bahr et al is broad, thorough and refreshing in its clear outline of the issues at hand. It emphasised the unique nature of the susceptible retinal ganglion cells [RGC] in LHON. It points out the lack of an established proven detailed pathophysiology of LHON in spite of human treatment trials already being performed. Thus, there is a requirement to do research on appropriate models, for example based on human induced pluripotential stem cell technology, of these particular types of RGCs and even on RGCs which are from genetic individuals. A broad range of research questions and approaches is suggested.
MERCS
Vianello et al [including IFOND board member Dr Carelli] in 2020 explore the Interaction between Mitochondrial DNA Variants and Mitochondria/Endoplasmic Reticulum Contact Sites [MERCS]. MERCS are a fundamental, yet under explored element in mitochondrial regulation likely relevant to the pathophysiology of various mitochondrial diseases. PMID:32598172.
Neuroplasticity
The incomplete loss of vision in those affected by LHON and the anecdotes of partial or complete visual recovery in LHON and other optic nerve and visual system insults gives hope for rehabilitation of the visual system in LHON. One recovery pathway may be to better understand and exploit the neuroplasticity of the central nervous system. Reviews of this area of active research are below.
Sabel BA, Gao Y, Antal A. Reversibility of visual field defects through induction of brain plasticity: vision restoration, recovery and rehabilitation using alternating current stimulation. Neural Regen Res. 2020 Oct;15(10):1799-1806. doi: 10.4103/1673-5374.280302. PMID: 32246620.
Castaldi E, Lunghi C, Morrone MC. Neuroplasticity in adult human visual cortex. Neurosci Biobehav Rev. 2020 May;112:542-552. doi: 10.1016/j.neubiorev.2020.02.028. Epub 2020 Feb 21. PMID: 32092315.
Biomolecular condensates
Absent from the retinal ganglion cell literature so far are relatively new concepts of biomolecular condensates and intracellular phase separation affected by interfacial water and mitochondrial matrix viscosity. Various light spectra and melatonin are known to affect these parameters. Research in dementia exploring these mechanisms may be relevant.
Loh, D.; Reiter, R.J. Light, Water, and Melatonin: The Synergistic Regulation of Phase Separation in Dementia. Int. J. Mol. Sci. 2023, 24, 5835. https://doi.org/10.3390/ijms24065835
Banani SF, Lee HO, Hyman AA, Rosen MK. Biomolecular condensates: organizers of cellular biochemistry. Nat Rev Mol Cell Biol. 2017 May;18(5):285-298. doi: 10.1038/nrm.2017.7. Epub 2017 Feb 22. PMID: 28225081; PMCID: PMC7434221.https://doi.org/10.1038%2Fnrm.2017.7
Diet/Lifestyle/Environment
Somewhat against the grain of the narrow drug centred 'silver bullet' paradigm currently dominating medical research and therapy is another call for long overdue research on the safety and efficacy of diet therapy. For example, not enough research on ketogenic diets in LHON has occurred since Douglas Wallace's proposal in 2010, 'Mitochondrial Energetics and Therapeutics', where he outlines and critiques metabolic therapies for mitochondrial diseases to date and discusses the revival of ketogenic diets and a more systemic approach as potential therapy. This approach is gaining popularity in many major diseases. So it is important for LHON carriers to know if this approach is safe for them and possibly preventative for various illness including LHON. Maybe a mouse fodder trial is the next step? Maybe survey of insulin resistance in LHON carriers and affected? Coffee anyone? Since we know Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy, shouldn't we find all avenues to support it?
Layrolle P, Orssaud C, Leleu M, Payoux P, Chavanas S. The Optic Nerve at Stake: Update on Environmental Factors Modulating Expression of Leber's Hereditary Optic Neuropathy. Biomedicines. 2024 Mar 6;12(3):584. doi: 10.3390/biomedicines12030584. PMID: 38540197; PMCID: PMC10968140.
Some research on the benefits of ketosis on the optic nerve and nervous system (then caution followed by coffee)
Storoni M, Robert MP, Plant GT. The therapeutic potential of a calorie-restricted ketogenic diet for the management of Leber hereditary optic neuropathy. Nutr Neurosci. 2019 Mar;22(3):156-164. doi: 10.1080/1028415X.2017.1368170. Epub 2017 Oct 10. PMID:28994349 DOI: 10.1080/1028415X.2017.1368170
Zarnowski T, Tulidowicz-Bielak M, Zarnowska I, Mitosek-Szewczyk K, Wnorowski A, Jozwiak K, Gasior M, Turski WA. Kynurenic Acid and Neuroprotective Activity of the Ketogenic Diet in the Eye. Curr Med Chem. 2017;24(32):3547-3558. doi: 10.2174/0929867324666170509120257. PMID: 28486923 DOI: 10.2174/0929867324666170509120257
Harun-Or-Rashid M, Pappenhagen N, Palmer P, Smith MA, Gevorgyan V, Wilson GN, Crish SD, Inman DM. Structural and Functional Rescue of Chronic Metabolically Stressed Optic Nerves through Respiration. J Neurosci. 2018 May 30;38(22):5122-5139. doi: 10.1523/JNEUROSCI.3652-17.2018. Epub 2018 May 14. PMID: 29760184