Novel therapeutic approaches for Leber's hereditary optic neuropathy.
Novel therapeutic approaches for Leber's hereditary optic neuropathy.
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作者：
S. Iyer
许多人类童年线粒体疾病是由线粒体DNA异常和生物能量学改变引起的。这些异常跨越了大部分mtDNA，表明线粒体基因组上没有“独特”的位置，当删除或突变时产生疾病表型。这种多样性意味着线粒体基因型和临床表型之间的关系非常复杂。因此，临床表型的起源尚不清楚，从根本上难以治疗，并且通常在临床上具有破坏性。目前的治疗在很大程度上是支持性的，疾病不断发展，导致显著的发病率和死亡率。在个别病例和临床试验中使用了维生素补充剂和药物制剂，但这些干预措施的效果尚不清楚。尽管最近在了解线粒体疾病的发病机制方面取得了进展，但治疗方法仍然难以捉摸。最佳的治疗方法是基因治疗，将缺失的基因引入线粒体以补充缺陷。我们最近的研究结果表明了一种创新的蛋白质转导（“protofection”）技术的可行性，该技术由重组线粒体转录因子a （TFAM）组成，该转录因子a可以有效地结合mtDNA，并允许在原位和体内有效地靶向线粒体。因此，治疗线粒体疾病的基因疗法的发展提供了希望，因为它可以避免临床异常和目前无法治疗受影响个体的个体疾病。这篇综述的目的是关注线粒体疾病治疗的当前治疗选择和未来的治疗方法，特别强调Leber遗传性视神经病变。
Many human childhood mitochondrial disorders result from abnormal mitochondrial DNA (mtDNA) and altered bioenergetics. These abnormalities span most of the mtDNA, demonstrating that there are no "unique" positions on the mitochondrial genome that when deleted or mutated produce a disease phenotype. This diversity implies that the relationship between mitochondrial genotype and clinical phenotype is very complex. The origins of clinical phenotypes are thus unclear, fundamentally difficult-to-treat, and are usually clinically devastating. Current treatment is largely supportive and the disorders progress relentlessly causing significant morbidity and mortality. Vitamin supplements and pharmacological agents have been used in isolated cases and clinical trials, but the efficacy of these interventions is unclear. In spite of recent advances in the understanding of the pathogenesis of mitochondrial diseases, a cure remains elusive. An optimal cure would be gene therapy, which involves introducing the missing gene(s) into the mitochondria to complement the defect. Our recent research results indicate the feasibility of an innovative protein-transduction ("protofection") technology, consisting of a recombinant mitochondrial transcription factor A (TFAM) that avidly binds mtDNA and permits efficient targeting into mitochondria in situ and in vivo. Thus, the development of gene therapy for treating mitochondrial disease offers promise, because it may circumvent the clinical abnormalities and the current inability to treat individual disorders in affected individuals. This review aims to focus on current treatment options and future therapeutics in mitochondrial disease treatment with a special emphasis on Leber's hereditary optic neuropathy.