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October 20—Phenylbutyrate, Approved for a Rare Metabolic Disorder in Infants, Appears Promising for Parkinson’s



CHICAGO—Phenylbutyrate, a life-saving drug approved for a rare metabolic disorder in infants, has potential as a new treatment for Parkinson’s disease (PD), according to a study that was presented here on Saturday at the Society for Neuroscience annual meeting.


Scientists at the University of Colorado had previously found that phenylbutyrate stops PD progression in mice; in a pilot trial, they gave it to 20 people in the early stages of PD and 20 age-matched healthy controls. At the meeting, they reported that a liquid version of the drug was well tolerated when given daily for three weeks, and it increased levels of alpha-synuclein in the bloodstream of both patients with PD and controls.


“We did not expect to see any effects on clinical status during this brief trial, but we wanted to see how the drug was tolerated and how much it could mobilize alpha-synuclein from the brain into the bloodstream,” the lead study author, Curt Freed, MD, head of the division of clinical pharmacology and toxicology and a professor of medicine at the University of Colorado School of Medicine, told the Neurology Today Conference Reporter.


“In our mouse model, the blood levels of alpha-synuclein doubled as the brain concentrations fell. Obviously, we don’t know what is going on inside human brains, but this is exciting enough to start planning a double-blind clinical trial in patients with newly diagnosed Parkinson’s.”


Dr. Freed and Wenbo Zhou, PhD, an assistant professor of medicine, had been working with a PD gene called DJ-1 that regulates many cellular stress responses. A mutated DJ-1 gene was identified in 2003 in an Italian family with three of 12 adult children who developed PD. The Colorado scientists conducted studies that showed that overexpressing DJ-1 protects cells from toxic stress responses.


By 2006, convinced that increased amounts of DJ-1 might protect people against PD, Dr. Freed and Dr. Zhou conducted a drug screen to identify possible drugs that could increase gene expression of DJ-1. They identified phenylbutyrate, which was already approved by the US Food and Drug Administration (FDA) for the treatment of urea cycle disorders.


In a transgenic mouse model that expresses a mutant form of alpha-synuclein, the mice developed normally until they were about 12 months old, but then the accumulated protein began to affect their movements and ability to carry out complex tasks.


When phenylbutyrate was added to their drinking water, they didn’t develop any PD symptoms, Drs. Freed and Zhou reported in the Journal of Biological Chemistry in 2011. The animals that did not have the drug in their drinking water had large Lewy body deposits in all of their neurons. The treated animals had no such pathology.


The dose of the drug is very high — 20 grams per day in adults. In pill form, this amounts to swallowing 40 tablets per day, a daunting challenge for PD patients, who often have difficulty swallowing. The FDA approved a liquid version of the drug in 2013 that could be taken as one teaspoonful three times per day with meals. The scientists began enrolling patients in a clinical trial funded by the Michael J. Fox Foundation. They treated 20 patients who were newly diagnosed and not yet taking levodopa and an equal number of controls.


“Since our research in mice has shown that alpha-synuclein in the blood plasma only comes from nerve cells, we think that the increase of alpha-synuclein in the blood is an indication that phenylbutyrate is improving clearance of brain alpha-synuclein in people just as it has done in mice,” said Dr. Freed. “This is a new concept for treating PD.”


He said that the drug works by upregulating the neuroprotective gene DJ-1. This gene activation leads to an increase in lysosome and exosome activity, promoting transfer of alpha-synuclein from neurons into the bloodstream, where the protein is eliminated.


“The idea that clearance of bad proteins in the brain will improve the symptoms of Parkinson’s disease and affect disease progression has been of great interest to scientists and to clinicians,” said Michael S. Okun, MD, FAAN, interim chair and professor of neurology at the University of Florida and the national medical director of the National Parkinson Foundation.


“Drug-based therapies like phenylbutyrate and nilotinib, as well as vaccines, have emerged as novel approaches for new therapeutics in Parkinson’s disease,” he said. “The big question for the field is whether clearing these proteins will translate into meaningful improvements and will delay disease progression. Large and carefully controlled trials will be required.”




· Freed C, et al. Phenylbutyrate response as a biomarker for alpha-synuclein clearance from the brain:

·        Zhou W, et al. Phenylbutyrate up-regulates the DJ-1 protein and protects neurons in cell culture and in animal models of Parkinson disease. J Biol Chem 2011; 286: 14941-14951: