Idebenone treatment in Leber's hereditary optic neuropathy: rationale and efficacy

Gueven, Nuri; Faldu, Dharmesh

doi:10.1517/21678707.2013.772894

Cited by 7 publications

(7 citation statements)

References 61 publications

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“…Ubiquinone is a fat-soluble molecule present at a very high concentration within the inner mitochondrial membrane and it has the advantageous property of transferring electrons efficiently from complexes I and II to complex III [60]. Co-enzyme Q10 (CoQ 10 ) is a synthetic ubiquinone analogue and despite the limited evidence base, it is frequently prescribed to patients with mitochondrial disease.…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

A neurodegenerative perspective on mitochondrial optic neuropathies

et al. 2016

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Mitochondrial optic neuropathies constitute an important cause of chronic visual morbidity and registrable blindness in both the paediatric and adult population. It is a genetically heterogeneous group of disorders caused by both mitochondrial DNA (mtDNA) mutations and a growing list of nuclear genetic defects that invariably affect a critical component of the mitochondrial machinery. The two classical paradigms are Leber hereditary optic neuropathy (LHON), which is a primary mtDNA disorder, and autosomal dominant optic atrophy (DOA) secondary to pathogenic mutations within the nuclear gene OPA1 that encodes for a mitochondrial inner membrane protein. The defining neuropathological feature is the preferential loss of retinal ganglion cells (RGCs) within the inner retina but, rather strikingly, the smaller calibre RGCs that constitute the papillomacular bundle are particularly vulnerable, whereas melanopsin-containing RGCs are relatively spared. Although the majority of patients with LHON and DOA will present with isolated optic nerve involvement, some individuals will also develop additional neurological complications pointing towards a greater vulnerability of the central nervous system (CNS) in susceptible mutation carriers. These so-called “plus” phenotypes are mechanistically important as they put the loss of RGCs within the broader perspective of neuronal loss and mitochondrial dysfunction, highlighting common pathways that could be modulated to halt progressive neurodegeneration in other related CNS disorders. The management of patients with mitochondrial optic neuropathies still remains largely supportive, but the development of effective disease-modifying treatments is now within tantalising reach helped by major advances in drug discovery and delivery, and targeted genetic manipulation.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1625-2) contains supplementary material, which is available to authorized users.

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Section: Therapeutic Strategiesmentioning

confidence: 99%

A neurodegenerative perspective on mitochondrial optic neuropathies

et al. 2016

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“…66,67 Idebenone and EPI-743 are newer generation shorter-chain analogues of ubiquinone that are reported to be more potent compared with CoQ10, at least in vitro, making them attractive candidate disease-modifying drugs for mitochondrial optic neuropathies. 68,69 RHODOS (Rescue of Hereditary Optic Disease Outpatient Study) was a multicenter double-blind randomized controlled trial set up to investigate the safety and efficacy of idebenone in LHON. Recruitment took place in the United Kingdom, Germany, and Canada, and 85 patients with a confirmed primary mtDNA LHON mutation (m.3460G > A, m.11778G > A, or m.14484T > C) were randomized in a 2:1 ratio to either idebenone (900 mg/d) or placebo over a 24-week treatment period.…”

Section: Quinone Analoguesmentioning

confidence: 99%

Therapeutic Approaches to Inherited Optic Neuropathies

Yu‐Wai‐Man

2015

Semin Neurol

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As a group, inherited optic neuropathies represent an important cause of severe irreversible visual loss among children and young adults. Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA) are the two most common forms encountered in clinical practice and several shared disease pathways have emerged that contribute to retinal ganglion cell loss, and eventually visual failure. In this review, the author critically appraises the evidence base for the various therapeutic strategies that have been put forward to treat these two mitochondrially determined optic neuropathies, including future developments. Innovative in vitro fertilization techniques to prevent female carriers of childbearing age from transmitting pathogenic mitochondrial DNA mutations to their biological children will also be discussed.

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“…Consistent with this hypothesis, a number of studies and trials suggested that idebenone could have a therapeutic effect in LHON patients [50,51] and provided the rationale for the first randomized, placebo-controlled study in LHON (NCT01421381) [52,53]. In this trial, idebenone improved visual acuity particularly in LHON patients with recent disease onset but not in patients of the placebo group [52,53].…”

Section: Short-chain Quinonesmentioning

confidence: 81%

Optic Neurodegeneration: Time to Act

Gueven¹

2014

Biol Med (Aligarh)

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Optic neuropathies are frequently associated with mitochondrial dysfunction and the associated vision loss has a severe impact on the patient's quality of life. Our understanding of disease progression of one of the most frequent mitochondrial disorders, Leber's hereditary optic neuropathy (LHON), together with results of recent clinical trials might provide us with new insights that are relevant not only to the progression of the disease but more importantly also for therapeutic intervention. One of the crucial hallmarks of LHON is the occasional recovery of vision in some patients. This rare and spontaneous process highlights that blindness in LHON patients is not irreversible per se and suggests that this process could potentially be induced by pharmacological intervention. Strikingly, spontaneous recovery of vision has been reported in some patients several years after disease onset, which indicates the presence of an extended time window where recovery is still possible, before over time the terminal loss of retinal neurons renders visual recovery impossible. Several recent encouraging trials in LHON and related disorders support this view and extend this model to other optic neuropathies that are not associated with spontaneous recovery. This concept provides hope not only to mitochondrial optic neuropathy patients, but also to patients that suffer from one of the major ocular disorders such as glaucoma.

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Idebenone treatment in Leber's hereditary optic neuropathy: rationale and efficacy

Cited by 7 publications

References 61 publications

A neurodegenerative perspective on mitochondrial optic neuropathies

A neurodegenerative perspective on mitochondrial optic neuropathies

Therapeutic Approaches to Inherited Optic Neuropathies

Optic Neurodegeneration: Time to Act

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