Current and Emerging Therapies for Leber Hereditary Optic Neuropathy

Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA disorder, presenting typically as a sequential, painless, subacute, optic neuropathy in young males. Despite the very limited therapeutic options in LHON, recent developments involving novel pharmacological agents and emerging gene therapy interventions have shown promising results for improved visual outcomes. A synthetic analogue of coenzyme Q (idebenone) is the most common medical treatment in LHON. In a multicentre, double-blind randomized, placebo-controlled clinical trial (Rescue of Hereditary Optic Disease Outpatient Study [RHODOS]), a dose of 900 mg/day of idebenone for 24 weeks was found to be well tolerated and safe. In a follow-up study (RHODOS-OFU), the visual acuity of 70% of patients enrolled in RHODOS was reassessed 30 months after discontinuation of idebenone. Results from this study suggested that visual acuity continued to improve even after discontinuation of the drug. Gene therapy has recently emerged as a potential treatment for LHON. RESCUE and REVERSE were two phase III clinical trials of viral-mediated gene therapy using lenadogene nolparvovec intravitreal injections in patients with early-stage LHON. Results in these trials have shown long-term safety and bilateral visual acuity improvement after unilateral intravitreal injections at 96 weeks, and sustained visual improvement after 3 years of treatment. The most recent phase III clinical trial in LHON (REFLECT) has shown significant improvement of vision after bilateral intravitreal injections of lenadogene nolparvovec compared with unilateral injections. These promising results suggest that, in the near future, LHON might become the first mitochondrial disorder to benefit from gene therapy.