Objective/Rationale:
In our previous research, we have discovered that a drug called phenylbutyrate can turn on a protective gene in the brain and can prevent Parkinson’s disease (PD) in models that are genetically programmed to get the disease. The drug works by transferring abnormal proteins from brain cells into the bloodstream. We now want to see if the drug works in patients with Parkinson’s in the same way. If it does, the drug may be able to stop the progression of Parkinson’s disease.
Project Description:
We will recruit 20 Parkinson’s patients who have been recently diagnosed and who are not taking any PD medications. We will draw blood and test it for brain proteins that are associated with Parkinson’s disease. Patients will then start taking the liquid drug phenylbutyrate-triglyceride, which has recently received FDA approval for a condition unrelated to Parkinson’s disease. Over the next four weeks, patients will have their blood tested a total of six times. We expect that the drug will increase the concentration of certain brain proteins in their blood.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
At the present time, there is no treatment that can slow or stop the progression of Parkinson’s disease. Drugs such as levodopa/carbidopa or even deep brain stimulation therapy treat the symptoms of Parkinson’s disease, not the underlying cause. Our research will see if we can stop one of the primary causes of Parkinson’s disease, accumulation of abnormal proteins in dopamine neurons. If this study is successful, then phenylbutyrate-triglyceride should be tested in a large trial of patients to see if can actually stop Parkinson’s disease from getting worse.
Anticipated Outcome:
Based on the work we have done with models, we expect that phenylbutyrate-triglyceride will promote removal of abnormal proteins from the brain into the bloodstream of some but not all Parkinson patients. We think that those patients will be the ones most likely to benefit from taking the drug long-term. Results from our study will be critical to determine whom to include in a definitive trial aimed at stopping the progression of Parkinson’s disease.
Final Outcome
In Parkinson's disease, a protein called alpha-synuclein produces abnormal deposits in dopamine neurons that can kill these important brain cells. Our lab has discovered that the drug phenylbutyrate can prevent these protein deposits from occurring in pre-clinical models that are genetically programmed to get Parkinson's as they age. The drug turns on a protective gene in the brain that pushes alpha-synuclein out of the brain and into the bloodstream where it can be eliminated. To see if phenylbutyrate has the same effect in people, we gave the drug for three weeks to 20 people with Parkinson's and 20 people without Parkinson's. We found that the drug increased the level of alpha-synclein in the bloodstream of all 40 people, strongly suggesting that the drug can stop alpha-synuclein from damaging dopamine neurons. The next step will be to give phenylbutyrate for a longer period, at least one year, to people with Parkinson's. To prove that the drug is stopping the disease, an equal number of people with Parkinson's will get a placebo drug. Comparing symptoms after one year in the treated patients with the placebo patients will determine whether phenylbutyrate can stop progression of Parkinson's.