Phenylbutyrate May Be Repurposed to Treat Lactic Acidosis

Ricki Lewis, PhD

March 06, 2013

A drug used to treat one inborn error of metabolism may be effective against another, according to a study published online March 6 in Science Translational Medicine.

Rosa Ferriero, from the Telethon Institute of Genetics and Medicine, Naples, Italy. and colleagues used healthy and abnormal human cells, mice, and zebrafish to demonstrate the ability of phenylbutyrate to treat lactic acidosis. Phenylbutyrate is already used to treat a related metabolic disorder, maple syrup urine disease.

Mutations in genes encoding any of the 3 pyruvate dehydrogenase complex (PDHC) enzymes are inborn errors of mitochondrial energy metabolism. They can cause neurological degeneration and excess lactate in the blood and cerebrospinal fluid. PDHC deficiency currently has no treatment.

Given similarities between the biochemistry involved in maple syrup urine disease and PDHC, the researchers hypothesized that the drug might be effective in patients with PDHC deficiency.

The researchers found that phenylbutyrate increased PDHC enzyme activity in fibroblasts from patients with PDHC deficiency. Moreover, in a zebrafish model of PDHC deficiency, the drug restored enzyme levels and alleviated symptoms of lethargy and hyperpigmentation.

Phenylbutyrate also prevented lactic acidosis in mice in which the condition had been induced by removal of part of the liver. The drug increased enzyme levels in many tissues, including the brain, suggesting that it might be helpful in treating PDHC deficiency in humans.

However, clinical trials are necessary to demonstrate whether repurposing of phenylbutyrate can treat lactic acidosis in patients. "Given that phenylbutyrate is a drug already approved for use in humans, and its safety profile is well known, these findings have the potential to be rapidly translated to clinical trials for patients with PDHC deficiency," the researchers write.

The treatment may have wider applications, because lactic acidosis is a secondary effect of other pathologies. "Therefore, applications of phenylbutyrate could be extended to a broader range of mitochondrial cytopathies," the researchers hypothesize. The drug may also be helpful to alleviate lactate acidosis in nongenetic conditions, such as asphyxia, liver disease, and ischemia.

This work was supported the United Mitochondrial Disease Foundation, the Italian Telethon Foundation, the European Research Council, and FIRB-MERIT. The authors have disclosed no other relevant financial relationships.

Sci Transl Med. Published online March 6, 2013.