Emerging Mitochondrial Therapeutic Targets in Optic Neuropathies

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• 作者：M.I.G. Lopez Sanchez^a ; ^b ; J.G. Crowston^a ; ^b ; D.A. Mackey^c ; I.A. Trounce^a ; ^b ; ^{i.trounce@unimelb.edu.au" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AAV ; adeno-associated virus ; ADOA ; autosomal dominant optic atrophy ; Cas 9 ; CRISPR-associated protein 9 ; CoQ10 ; coenzyme Q10 ; CR ; caloric restriction ; CRISPR ; clustered regularly interspaced short palindromic repeats ; E2 ; 17β-estradiol ; ER ; estrogen receptor ; FADH2 ; flavin adenine dinucleotide ; IOP ; intra-ocular pressure ; iPSC ; induced pluripotent stem cell ; LHON ; Leber hereditary optic neuropathy ; MELAS ; mitochondrial encephalomyopathy ; lactic acidosis ; and stroke-like episodes ; MERRF ; myocloni
• 刊名：Pharmacology and Therapeutics
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：165
• 期：Complete
• 页码：132-152
• 全文大小：1268 K

文摘

Optic neuropathies are an important cause of blindness worldwide. The study of the most common inherited mitochondrial optic neuropathies, Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA) has highlighted a fundamental role for mitochondrial function in the survival of the affected neuron—the retinal ganglion cell. A picture is now emerging that links mitochondrial dysfunction to optic nerve disease and other neurodegenerative processes. Insights gained from the peculiar susceptibility of retinal ganglion cells to mitochondrial dysfunction are likely to inform therapeutic development for glaucoma and other common neurodegenerative diseases of aging. Despite it being a fast-evolving field of research, a lack of access to human ocular tissues and limited animal models of mitochondrial disease have prevented direct retinal ganglion cell experimentation and delayed the development of efficient therapeutic strategies to prevent vision loss. Currently, there are no approved treatments for mitochondrial disease, including optic neuropathies caused by primary or secondary mitochondrial dysfunction. Recent advances in eye research have provided important insights into the molecular mechanisms that mediate pathogenesis, and new therapeutic strategies including gene correction approaches are currently being investigated.

Here, we review the general principles of mitochondrial biology relevant to retinal ganglion cell function and provide an overview of the major optic neuropathies with mitochondrial involvement, LHON and ADOA, whilst highlighting the emerging link between mitochondrial dysfunction and glaucoma. The pharmacological strategies currently being trialed to improve mitochondrial dysfunction in these optic neuropathies are discussed in addition to emerging therapeutic approaches to preserve retinal ganglion cell function.