Mitochondrial diseases: Therapeutic approaches
Mitochondrial diseases: Therapeutic approaches
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DOI：
10.1007/s10540-007-9041-4
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发表时间：
2007-06-01
影响因子：
4
通讯作者：
Mancuso, Michelangelo
中科院分区：
文献类型：
--
作者：
DiMauro, Salvatore;Mancuso, Michelangelo
线粒体脑肌病（严格定义为线粒体呼吸链缺陷）的治疗严重不足，尽管我们对这些疾病的分子基础的理解取得了很大进展。在这篇综述中，我们依次考虑几种不同的治疗方法。姑息治疗是由良好的医疗实践决定的，包括抗惊厥药物，控制内分泌功能障碍和外科手术。去除有害代谢物以对抗乳酸酸中毒为中心，但也延伸到其他代谢物。试图通过电子受体的管理来绕过呼吸链中的障碍还没有成功，但这可能是基因工程的结果。代谢物和辅助因子的管理是现实生活治疗的支柱，在由于特定化合物（如肉碱或辅酶Q10）的主要缺乏而引起的疾病中尤为重要。在原发性线粒体疾病和与线粒体功能障碍直接或间接相关的神经退行性疾病中，活性氧清除剂的应用越来越受到关注。有氧运动和物理治疗可以预防或纠正线粒体DNA （mtDNA）突变引起的线粒体肌病患者的去调节和提高运动耐受性。由于多质性和异质性，基因治疗是一个挑战，但有趣的实验方法正在被追求，包括，例如，减少突变与野生型线粒体基因组的比例（基因转移），将突变的mtDNA基因转化为正常的核DNA基因（异位表达），从其他物种导入同源基因，或用特定的限制性内切酶纠正mtDNA突变。生殖系治疗引起了伦理问题，但正在考虑用于预防mtDNA突变的母体传播。通过遗传咨询和产前诊断的预防性治疗对核dna相关疾病变得越来越重要。尽管还有许多工作要做，但每种方法的进展都为未来带来了一线希望。
Therapy of mitochondrial encephalomyopathies (defined restrictively as defects of the mitochondrial respiratory chain) is woefully inadequate, despite great progress in our understanding of the molecular bases of these disorders. In this review, we consider sequentially several different therapeutic approaches. Palliative therapy is dictated by good medical practice and includes anticonvulsant medication, control of endocrine dysfunction, and surgical procedures. Removal of noxious metabolites is centered on combating lactic acidosis, but extends to other metabolites. Attempts to bypass blocks in the respiratory chain by administration of electron acceptors have not been successful, but this may be amenable to genetic engineering. Administration of metabolites and cofactors is the mainstay of real-life therapy and is especially important in disorders due to primary deficiencies of specific compounds, such as carnitine or coenzyme Q10. There is increasing interest in the administration of reactive oxygen species scavengers both in primary mitochondrial diseases and in neurodegenerative diseases directly or indirectly related to mitochondrial dysfunction. Aerobic exercise and physical therapy prevent or correct deconditioning and improve exercise tolerance in patients with mitochondrial myopathies due to mitochondrial DNA (mtDNA) mutations. Gene therapy is a challenge because of polyplasmy and heteroplasmy, but interesting experimental approaches are being pursued and include, for example, decreasing the ratio of mutant to wild-type mitochondrial genomes (gene shifting), converting mutated mtDNA genes into normal nuclear DNA genes (allotopic expression), importing cognate genes from other species, or correcting mtDNA mutations with specific restriction endonucleases. Germline therapy raises ethical problems but is being considered for prevention of maternal transmission of mtDNA mutations. Preventive therapy through genetic counseling and prenatal diagnosis is becoming increasingly important for nuclear DNA-related disorders. Progress in each of these approaches provides some glimmer of hope for the future, although much work remains to be done.