{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:33:13Z","timestamp":1792787593145,"version":"4.5.0"},"reference-count":41,"publisher":"American Society for Clinical Investigation","issue":"18","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"U.S. Food and Drug Administration","award":["R01FD005407"],"award-info":[{"award-number":["R01FD005407"]}],"id":[{"id":"https:\/\/ror.org\/034xvzb47","id-type":"ROR","asserted-by":"crossref"}]},{"name":"College of Medicine, University of Florida","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"https:\/\/ror.org\/02y3ad647","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Saol Therapeutics","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,22]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>Dichloroacetate (DCA) is an orally administered structural analog of pyruvate, an endogenous pyruvate dehydrogenase kinase inhibitor.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      We conducted a phase III multicenter trial in 34 children with pyruvate dehydrogenase complex deficiency (PDCD). Participants were randomly allocated to 4 months of treatment with DCA or a placebo, followed by a 1-month washout period and crossover to the alternate arm, and could continue into an open-label extension period. DCA dosing was predetermined by pharmacogenomic analysis of\n                      <jats:italic>GSTZ1<\/jats:italic>\n                      , which modulates DCA metabolism. The primary endpoint was the observer-reported outcomes motor domain (ObsRO\n                      <jats:sub>motor<\/jats:sub>\n                      ) score. Additional assessments evaluated motor function, plasma lactate levels, and survival.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Chronic DCA was well tolerated and safe. The primary endpoint, ObsRO\n                      <jats:sub>motor<\/jats:sub>\n                      , was not statistically significantly different between the treatment and placebo groups (\n                      <jats:italic>P<\/jats:italic>\n                      = 0.512). However, longer-term treatment, including the open-label extension, showed a statistically significant treatment effect (\n                      <jats:italic>P<\/jats:italic>\n                      = 0.002), especially in participants with higher baseline motor impairment (ObsRO\n                      <jats:sub>motor<\/jats:sub>\n                      \u2265 8;\n                      <jats:italic>P<\/jats:italic>\n                      = 0.001). DCA decreased plasma lactate \u20130.48 (0.82) mmol\/L (\u201320%;\n                      <jats:italic>P<\/jats:italic>\n                      = 0.006). Survival of participants was significantly greater than that of a natural history cohort (log-rank\n                      <jats:italic>P<\/jats:italic>\n                      = 0.027).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>\n                      Longer-term treatment with DCA, dosed based on\n                      <jats:italic>GSTZ1<\/jats:italic>\n                      haplotype, is safe and was associated with a statistically significant improvement in patient motor function, plasma lactate, and survival.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>FUNDING<\/jats:title>\n                    <jats:p>NIH (R01FD005407; R42HD089804), University of Florida Department of Medicine, Saol Therapeutics.<\/jats:p>\n                  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USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Gropman","sequence":"additional","affiliation":[{"name":"Department of Genomic and Translational Neuroscience, St. Jude Children\u2019s Research Hospital, Memphis, Tennessee, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Hamm","sequence":"additional","affiliation":[{"name":"Saol Therapeutics, Roswell, Georgia, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenia","family":"Henry","sequence":"additional","affiliation":[{"name":"Firma Clinical Research, Elk Grove Village, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Longo","sequence":"additional","affiliation":[{"name":"Division of Clinical Genetics\/Human Genetics, UCLA, Los Angeles, California, 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