Developments in the Treatment of Leber Hereditary Optic Neuropathy

被引:18
|
作者
Chen, Benson S. [1 ,2 ,3 ]
Yu-Wai-Man, Patrick [1 ,2 ,3 ,4 ,5 ]
Newman, Nancy J. [6 ,7 ,8 ]
机构
[1] Univ Cambridge, John Van Geest Ctr Brain Repair, Cambridge CB2 0PY, England
[2] Univ Cambridge, MRC Mitochondrial Biol Unit, Dept Clin Neurosci, Cambridge CB2 0PY, England
[3] Cambridge Univ Hosp, Addenbrookes Hosp, Cambridge Eye Unit, Cambridge, England
[4] Moorfields Eye Hosp NHS Fdn Trust, London, England
[5] UCL, Inst Ophthalmol, London, England
[6] Emory Univ, Dept Ophthalmol, Sch Med, Atlanta, GA 30322 USA
[7] Emory Univ, Dept Neurol, Sch Med, Atlanta, GA 30322 USA
[8] Emory Univ, Dept Neurol Surg, Sch Med, Atlanta, GA 30322 USA
基金
美国国家卫生研究院;
关键词
Leber hereditary optic neuropathy; Optic atrophy; Mitochondrial disease; Gene therapy; Idebenone; Allotopic expression; LONG-TERM EFFICACY; GENE-THERAPY; COMPLEX-I; IDEBENONE; LHON; MITOCHONDRIA; MUTATIONS; EPI-743; MANIPULATION; EXPRESSION;
D O I
10.1007/s11910-022-01246-y
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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 Q(10) (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. Although approved treatments are presently limited, innovations in gene therapy and editing are driving the expansion of the therapeutic delivery pipeline for LHON.
引用
收藏
页码:881 / 892
页数:12
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