Leber’s hereditary optic neuropathy: new quinone therapies change the paradigm

Abstract

Leber’s hereditary optic neuropathy is a maternally inherited disease of the optic nerve prevalent in young adult males that usually leads to permanent and severe blindness. Three primary mitochondrial DNA (mtDNA) mutations affecting the respiratory complex I account for approximately 95% of cases. The mtDNA mutations are necessary but not sufficient to cause blindness. The incomplete penetrance is probably due to complex combinations of nuclear modifying genes, age and gender issues and specific environmental risk factors. The optic nerve is particularly susceptible to mitochondrial dysfunction, particularly the intra-retinal unmyelinated axons. There has been a dearth of effective treatments for this devastating cause of visual loss. Recently, there has been much progress in understanding the natural history and pathogenic mechanisms of Leber’s hereditary optic neuropathy. This has led to trials using quinones to overcome the complex I defect produced by the mtDNA mutations. Other therapies are also proposed, such as gene therapy.

Keywords::

• gene therapy
• idebenone
• Leber’s hereditary optic neuropathy
• mitochondria
• mitochondrial DNA
• optic nerve
• quinone
• therapy

Financial & competing interest disclosures

AA Sadun and V Carelli are the principal investigators of a clinical trial with a new quinone (EPI-743) for Leber’s hereditary optic neuropathy funded by Edison Pharmaceutical. They have no proprietary interests nor consulting fees. V Carelli received reimbursement for travel expenses. C La Morgia has a contract for a clinical trial sponsored by Sigma-Tau spa. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.