Clinical trials in Leber hereditary optic neuropathy: outcomes and opportunities

Purpose of review Leber hereditary optic neuropathy (LHON) is a mitochondrial DNA disease characterised by sequential bilateral vision loss due to loss of retinal ganglion cells. The purpose of this review is to provide an update on the results of recent clinical trials for LHON, focusing on studies of idebenone and lenadogene nolparvovec gene therapy. Recent findings Evidence from three clinical studies (RHODOS, RHODOS-OFU, and LEROS) suggest that idebenone should be started early and continued for at least 24 months. Treatment effect varies according to the stage of LHON and the underlying mutation. Favourable outcomes are associated with the m.11778G>A mutation and chronic eyes with the m.14484T>C mutation. Caution should be taken in subacute/dynamic eyes with the m.3460G>A mutation, due to possible clinical worsening with idebenone. Compared to eyes from an external natural history cohort, pooled data from four clinical studies (RESCUE, REVERSE, RESTORE and REFLECT) show that a single intravitreal injection of lenadogene nolparvovec can result in sustained bilateral visual improvement in m.11778G>A LHON patients aged ≥15 years when treated within 1 year of onset. Although the treatment effect is modest, the final visual acuity of treated patients (∼1.2 logMAR) significantly differs from the published natural history of LHON and the treatment benefit is more pronounced than the effect of idebenone alone in patients with the m.11778G>A mutation. Summary There is increasing evidence for the potential therapeutic benefit of idebenone and lenadogene nolparvovec gene therapy.