CLINICAL TRIAL: DICHLOROACETATE TREATMENT OF CONGENITAL LACTIC ACIDOSIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 DCA目前正在对GCRC进行关键的3期对照临床试验，GCRC是一种研究药物，已被食品和药物管理局指定为治疗先天性乳酸酸中毒(CLA)的孤儿产品。先天性乳酸酸中毒是一种罕见的先天性线粒体代谢错误，会导致细胞能量衰竭和过早死亡。DCA被认为有益于这种疾病的患者，因为它直接抑制线粒体丙酮酸脱氢酶(PDH)激酶，从而间接激活PDH复合体，促进乳酸的去除和底物燃料向能量的有效转化。 我们对DCA在体内生物转化机制的了解的最新进展，为人类慢性接触DCA的可能原因、治疗和预防提供了令人兴奋的新见解。这些新发现包括：1)深入了解DCA在体内和体外生物转化为乙醛的机制；2)确定DCA是哺乳动物酪氨酸代谢中的关键酶-马来酸乙酰乙酸酯异构酶(MAAI)的抑制剂；3)发现DCA抑制MAAI可导致酪氨酸分解代谢途径中中间体的积累，这可能与DCA的肝脏毒性和神经毒性有关；4)表明这种抑制作用也可能是延长后续剂量DCA消除半衰期的原因。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. DCA is currently undergoing a pivotal phase 3 controlled clinical trial on the GCRC as an investigational drug that has been designated by the Food and Drug Administration as an Orphan Product for congenital lactic acidosis (CLA), a collection of rare inborn errors of mitochondrial metabolism causing cellular energy failure and early death. DCA is postulated to benefit patients with this disease because it directly inhibits mitochondrial pyruvate dehydrogenase (PDH) kinase, thereby indirectly activating the PDH complex and facilitating both lactate removal and the efficient conversion of substrate fuel into energy. Recent advances in our understanding of the mechanisms of DCA biotransformation in vivo provide exciting new insight into the possible causes, treatment and prevention of the adverse effects of chronic DCA exposure in humans. These novel findings include: 1) gaining insight into the mechanisms by which DCA is biotransformed in vivo and in vitro to glyoxylate, 2) identifying DCA as an inhibitor of maleylacetoacetate isomerase (MAAI), a key enzyme in mammalian tyrosine metabolism, 3) discovering that MAAI inhibition by DCA may cause accumulation of intermediates in the tyrosine catabolic pathway that may be responsible for the hepatotoxicity and neurotoxicity of DCA and 4) showing this inhibition may also be responsible for prolonging the elimination half life of subsequent doses of DCA.