CLINICAL TRIAL: DICHLOROACETATE TREATMENT OF CONGENITAL LACTIC ACIDOSIS

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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 the open label phase of a 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: gaining insight into the mechanisms by which DCA is biotransformed in vivo and in vitro to glyoxylate; identifying DCA as an inhibitor of maleylacetoacetate isomerase-MAAI, a key enzyme in mammalian tyrosine metabolism; 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 showing this inhibition may also be responsible for prolonging the elimination half life of subsequent doses of DCA.