PDF(Pubmed)
Abstract：
UNASSIGNED: Genetic mitochondrial diseases are a major challenge in modern medicine, impacting around 1:4,000 individuals. Leigh syndrome is the most common pediatric presentation of mitochondrial disease. There are currently no effective clinical treatments for mitochondrial disease. In humans, patients are often treated with antioxidants, vitamins, and strategies targeting energetics. The vitamin-E related compound vatiquinone (EPI-743, α-tocotrienol quinone) has been the subject of at least 19 clinical trials in the US since 2012, but the effects of vatiquinone on an animal model of mitochondrial disease have not yet been reported. Here, assessed the impact of vatiquinone on disease progression and in two animal models of mitochondrial disease.
UNASSIGNED: The efficacy of vatiquinone in vitro was assessed using human fibroblasts treated with the general mitochondrial oxidative stress inducer paraquat, the GPX4 inhibitor RSL3, or the glutathione synthase inhibitor BSO in combination with excess iron. The therapeutic potential of vatiquinone in vivo was assessed using tamoxifen-induced mouse model for GPX4 deficiency and the Ndufs4 knockout mouse model of Leigh syndrome. In both models, animals were treated daily with vatiquinone or vehicle and relevant disease endpoints were assessed.
UNASSIGNED: Vatiquinone robustly prevented death in cultured cells induced by RSL3 or BSO/iron, but had no effect on paraquat induced cell death. Vatiquinone had no impact on disease onset, progression, or survival in either the tamoxifen-inducible GPX4 deficient model or the Ndufs4(-/-) mouse model, though the drug may have reduced seizure risk.
UNASSIGNED: Vatiquinone provided no benefit to survival in two mouse models of disease, but may prevent seizures in the Ndufs4(-/-) model. Our findings are consistent with recent press statements regarding clinical trial results and have implications for drug trial design and reporting in patients with rare diseases.
UNASSIGNED: The efficacy of vatiquinone in vitro was assessed using human fibroblasts treated with the general mitochondrial oxidative stress inducer paraquat, the GPX4 inhibitor RSL3, or the glutathione synthase inhibitor BSO in combination with excess iron. The therapeutic potential of vatiquinone in vivo was assessed using tamoxifen-induced mouse model for GPX4 deficiency and the Ndufs4 knockout mouse model of Leigh syndrome. In both models, animals were treated daily with vatiquinone or vehicle and relevant disease endpoints were assessed.
UNASSIGNED: Vatiquinone robustly prevented death in cultured cells induced by RSL3 or BSO/iron, but had no effect on paraquat induced cell death. Vatiquinone had no impact on disease onset, progression, or survival in either the tamoxifen-inducible GPX4 deficient model or the Ndufs4(-/-) mouse model, though the drug may have reduced seizure risk.
UNASSIGNED: Vatiquinone provided no benefit to survival in two mouse models of disease, but may prevent seizures in the Ndufs4(-/-) model. Our findings are consistent with recent press statements regarding clinical trial results and have implications for drug trial design and reporting in patients with rare diseases.
摘要：
背景遗传性线粒体疾病是现代医学的主要挑战,影响了大约1:4,000个人。Leigh综合征是线粒体疾病最常见的儿科表现。目前没有有效的线粒体疾病的临床治疗方法。在人类中,患者通常用抗氧化剂治疗，维生素,以及针对能量学的策略。自2012年以来，维生素E相关的化合物vatiquinol（EPI-743，α-生育三烯酚醌）已成为美国至少19项临床试验的主题，但vatiquinol对线粒体疾病动物模型的影响尚未报道。这里,在两种线粒体疾病动物模型中评估了vaticino醌对疾病进展的影响。方法采用一般线粒体氧化应激诱导剂百草枯处理的人成纤维细胞，评估万替醌的体外疗效。GPX4抑制剂RSL3或谷胱甘肽合酶抑制剂BSO与过量铁的组合。使用他莫昔芬诱导的GPX4缺乏小鼠模型和Leigh综合征的Ndufs4敲除小鼠模型评估万替醌在体内的治疗潜力。在这两种模型中，每天用vaticino醌或媒介物治疗动物，并评估相关疾病终点。结果Vatiquinium能强有力地防止RSL3或BSO/铁诱导的培养细胞死亡，但对百草枯诱导的细胞死亡没有影响。瓦蒂醌对疾病发作没有影响，programming,或在他莫昔芬诱导的GPX4缺陷模型或Ndufs4（-/-）小鼠模型中的存活，尽管这种药物可能降低了癫痫发作的风险。结论在两种小鼠疾病模型中，Vatiquinion对生存没有任何益处，但可以防止Ndufs4（-/-）模型中的癫痫发作。我们的发现与最近关于临床试验结果的新闻声明一致，并对罕见疾病患者的药物试验设计和报告具有意义。
