Journal
ADVANCED DRUG DELIVERY REVIEWS
Volume 60, Issue 13-14, Pages 1478-1487Publisher
ELSEVIER
DOI: 10.1016/j.addr.2008.02.014
Keywords
Dichloroacetate; Mitochondria; Pyruvate dehydrogenase; Gene therapy; Pharmacogenetics; Pharmacotoxicology; Drug metabolism
Categories
Funding
- NIH [M01000032, ES007355, ES014617]
- Zachary Foundation
- NATIONAL CENTER FOR RESEARCH RESOURCES [M01RR000082, M01RR000032] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [R01ES014617, R01ES007355] Funding Source: NIH RePORTER
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Dichloroacetate (DCA) is an investigational drug for the treatment of genetic mitochondrial diseases. Its primary site of action is the pyruvate dehydrogenase (PDH) complex, which it stimulates by altering its phosphorylation state and stability. DCA is metabolized by and inhibits the bifunctional zeta-1 family isoform of glutathione transferase/maleylacetoacetate isomerase. Polymorphic variants of this enzyme differ in their kinetic properties toward DCA, thereby influencing its biotransformation and toxicity, both of which are also influenced by subject age. Results from open label studies and controlled clinical trials suggest chronic oral DCA is generally well-tolerated by young children and may be particularly effective in patients with PIDH deficiency. Recent in vitro data indicate that a combined DCA and gene therapy approach may also hold promise for the treatment of this devastating condition. (C) 2008 Elsevier B.V. All rights reserved.
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