Leber Hereditary Optic Neuropathy (LHON) is a significant contributing factor behind the increasing blindness burden among young population. The birth LHON prevalence is approximately 1 in 50,000 people as estimated by the Rare Disease Database.

Leber Hereditary Optic Neuropathy is a common inherited condition characterized by vision loss.  A painless loss of central vision is a mitochondrial disorder, it primarily affects males during young-adult age. Due to an optic nerve dysfunction as a result of mutations in the mitochondrial DNA, LHON is transmitted in a non-Mendelian pattern degenerating retinal ganglion cells and optic nerves significantly.  

LHON, at first, causes a loss in one eye, followed by the other in a few months. However, there have been cases when the loss in both the eyes is reported due to Leber Hereditary Optic Neuropathy. A characteristic manifestation of LHON can be both ophthalmologic and extra-ocular. Since it is maternally inherited, both male and female offspring can inherit.

Leber Hereditary Optic Neuropathy Epidemiology

Several LHON Epidemiology studies revealed a higher male preponderance. Researchers believe that this may be due to the mutation in the recessive X-linked susceptibility gene. According to scientific literature authored by Saranya et al., male predominance of around 86% was reported. A study authored by Meyerson et al. presented that Leber Hereditary Optic Neuropathy rarely causes a loss in vision after the age of 50 years, however, there have been a few reported cases.
Another LHON Epidemiology survey observed that of all the mutated inheritance of Leber Hereditary Optic Neuropathy cases, 50% of the males and only 10% of the females experience vision loss.

Leber hereditary optic neuropathy incidence is reported to be about 1 in 25,000 of the UK population according to a study conducted by P Y W Man et al. Interestingly enough, over 95% of LHON cases are primarily the result of one of three mitochondrial DNA (mtDNA) point mutations, G3460A, G11778A, and T14484C, and all of them involve genes encoding complex I subunits of the respiratory chain.

Leber Hereditary Optic Neuropathy Treatment landscape

The mainstay of Leber Hereditary Optic Neuropathy clinical treatment remains supportive rather than curative. The LHON management includes low vision aids, occupational rehabilitation and registration with local social services. Nutritional supplements, several combinations of vitamins (e.g., B2, B3, B12, C, E, and folic acid) and other supplements such as alpha-lipoic acid, carnitine, creatine, L-arginine, and dichloroacetate have been tried to treat mitochondrial disorders, including LHON.

The mtDNA mutations destabilize complex I of the respiration leading to a reduction in ATP levels and increase in ROS levels. Ubiquinone analogues play a major role in the electron transfer along the mitochondrial respiratory chain. The mainstay principle of using ubiquinone analogues is to restore the flow of electrons and bypassing the blockage at the level of complex I, thereby shunting the electrons directly to complex III. However, analyses have shown little proof of efficacy with these interventions.

EMA approved Leber Hereditary Optic Neuropathy therapies include Raxone (idebenone) for the treatment of visual impairment in adolescent and adult patients. Another LHON therapy, proven to show a synergistic RGC neuroprotective effect, is Brimonidine. It, therefore, can potentially be useful in asymptomatic LHON carriers with glaucoma due to its pressure-lowering effects and putative neuroprotective effects.
Along with the above mentioned LHON therapies, alternative therapies such as steroids and immunosuppressant like cyclosporine A are being tried in the LHON treatment. Hyperbaric oxygen therapy (HBOT), believed to increase the oxygen levels in retinal ganglion cells, is also being tested in patients with optic neuropathies such as radiation neuropathy along with the acute phase of LHON.

Furthermore, Nearinfrared light (NIR) therapy has been shown to improve mitochondrial function and cellular survival in various models of wound healing, neurodegeneration and methanol-induced retinal toxicity.
Leber Hereditary Optic Neuropathy Treatment options are limited. The LHON treatment stage is still in its initial stages, even though there is promising research underway. Gene therapy trials are also currently underway for LHON treatment.
Key Pharma and Biotech players, such as GenSight, Stealth BioTherapeutics, Ixchel Pharma and others are in the process of developing potential therapies for the of Leber’s Hereditary Optic Neuropathy treatment. The launch of LHON emerging therapies, such as GS010 (GenSight), Elamipretide (Stealth BioTherapeutics) and others are expected to significantly impact the Leber’s Hereditary Optic Neuropathy treatment scenario of in the upcoming years.

GS010 a lead candidate of GenSight, is an AAV2 gene therapy vector that encodes the human wild-type ND4 protein. GenSight is conducting two phase III studies for the treatment of Leber Hereditary Optic Neuropathy in various territories of the US and Europe. It has also received Orphan Drug Designation both in the United States and in Europe.
Stealth Biotherapeutics is running clinical trials of Elamipretide, which is a peptide compound that readily penetrates cell membranes and targets the inner mitochondrial membrane where it binds reversibly to cardiolipin. This elamipretidecardiolipin association has been shown to normalize the structure of the inner mitochondrial membrane, thereby improving mitochondrial function. Stealth BioTherapeutics is evaluating the drug in phase II clinical trial for the Leber’s hereditary optic neuropathy treatment. Company is also conducting clinical trials for other indications such as primary mitochondrial myopathy, Barth syndrome and others.

DelveInsight estimates that the overall rise in research and development and the progress of emerging therapies shall drive the overall Leber’s Hereditary Optic Neuropathy market during the forecast period [2019–2028].
Also, due to an increasing Leber’s Hereditary Optic Neuropathy prevalence, it becomes crucial to evaluate the disorder correctly and detect the underlying exact causes. This will along with accelerating better LHON diagnosis rates will also prevent in the further transmission of the disorder to offspring. The newly emerging LHON treatment modalities such as gene therapy, stem cells and others may be a ray of hope for the individuals with these mutations.