Developments in the Treatment of Leber Hereditary Optic Neuropathy

• Type of Material: Article
• Authors: Nancy Newman, Emory University; Benson S Chen, University of Cambridge; P Yu-Wai-Man, University of Cambridge
• Language: English
• Date: 2022-11-21
• Publisher: SPRINGER
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1007/s11910-022-01246-y
• Title of Journal or Parent Work: CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS
• Volume: 22
• Issue: 12
• Start Page: 881
• End Page: 892
• Keywords: Idebenone; EXPRESSION; IDEBENONE; Allotopic expression; GENE-THERAPY; MUTATIONS; Mitochondrial disease; MANIPULATION; Leber hereditary optic neuropathy; Neurosciences; Science & Technology; LONG-TERM EFFICACY; LHON; Optic atrophy; COMPLEX-I; Neurosciences & Neurology; EPI-743; Gene therapy; MITOCHONDRIA; Life Sciences & Biomedicine; Clinical Neurology
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Purposeof Review: To outline the current landscape of treatments for Leber hereditary optic neuropathy (LHON) along the therapeutic delivery pipeline, exploring the mechanisms of action and evidence for these therapeutic approaches. Recent Findings: Treatments for LHON can be broadly classified as either mutation-specific or mutation-independent. Mutation-specific therapies aim to correct the underlying mutation through the use of a gene-editing platform or replace the faulty mitochondrial DNA-encoded protein by delivering the wild-type gene using a suitable vector. Recent gene therapy clinical trials assessing the efficacy of allotopically expressed MT-ND4 for the treatment of LHON due to the m.11778G > A mutation in MT-ND4 have shown positive results when treated within 12 months of symptom onset. Mutation-independent therapies can have various downstream targets that aim to improve mitochondrial respiration, reduce mitochondrial stress, inhibit or delay retinal ganglion cell apoptosis, and/or promote retinal ganglion cell survival. Idebenone, a synthetic hydrosoluble analogue of co-enzyme Q10 (ubiquinone), is the only approved treatment for LHON. Mutation-independent approaches to gene therapy under pre-clinical investigation for other neurodegenerative disorders may have the potential to benefit patients with LHON. Summary: Although approved treatments are presently limited, innovations in gene therapy and editing are driving the expansion of the therapeutic delivery pipeline for LHON.