another abstract from Joanie McGuire
Program#/Poster#:
12.02
Presentation Title:
Stopping progression of Parkinson's disease with the drug phenylbutyrate
Location:
N230
Presentation time:
Saturday, Oct 17, 2015, 1:15 PM - 1:30 PM
Topic:
++C.03.a. Human studies
Authors:
*C. R. FREED1, M. WANG1, J. CUMMISKEY1, K. B. BJUGSTAD1, B. A. SYMMES1, C. A. JOHNSON2, R. C. MURPHY2, M. A. LEEHEY3, W. ZHOU1;
1Div. of Clin. Pharmacol., 2Dept. of Pharmacol., 3Dept. of Neurol., Univ. Colorado Sch. of Med., Aurora, CO
Abstract:
Parkinson's disease has excellent symptomatic treatment with drugs such as L-DOPA, but the underlying disease process causes a relentless downhill course.
Several drugs have been tested in an effort to alter disease progression, but all have failed. We have developed a new concept for stopping the progression of Parkinson’s disease by turning on a neuroprotective gene with an FDA-approved drug. In Parkinson’s disease, the protein alpha-synuclein forms abnormal deposits called Lewy bodies as well as toxic fibrils which contribute to the death of dopamine neurons. We have discovered that the drug phenylbutyrate can prevent aggregation of alpha-synuclein in transgenic mice which are genetically programmed to develop a form of Parkinson’s disease as they age.
The drug works by upregulating the neuroprotective gene DJ-1. 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. In mice, phenylbutyrate increased plasma alpha-synuclein by about 100 per cent compared to non-treated control animals.
To see if phenylbutyrate has the same effect in people, we have given the drug for three weeks to 20 people with newly diagnosed Parkinson’s disease and to 20 age-matched subjects without the disease. We found that the drug increased the level of alpha-synclein in plasma of all 40 subjects from 50 to 150 per cent of baseline values, just as it had done in transgenic mice, strongly suggesting that the drug can mobilize alpha-synuclein from neurons into blood plasma. While baseline plasma alpha-synuclein varied between subjects, the average alpha-synuclein plasma concentrations at baseline and during phenylbutyrate administration did not differ between patients with Parkinson's disease and normal subjects. Results are compatible with a neuroprotective effect of phenylbutyrate by accelerating clearance of alpha-synuclein from brain into plasma.
A double-blind, placebo-controlled trial in newly diagnosed Parkinson patients will be needed to prove whether phenylbutyrate can stop the progression of Parkinson’s disease in humans.
Disclosures:
C.R. Freed: C. Other Research Support (receipt of drugs, supplies, equipment or other in-kind support); Hyperion Pharmaceuticals. M. Wang: None. J. Cummiskey: None. K.B. Bjugstad: None. B.A. Symmes:None. C.A. Johnson: None. R.C. Murphy: None. M.A. Leehey: None. W. Zhou: None.
Keyword (s):
PARKINSON'S DISEASE
NEUROPROTECTION
DOPAMINE
Support:
Walter S. and Lucienne Driskill Foundation
Michael J. Fox Foundation
Mr. Charles Ackerman
Mr. Ray Sidhom
Mr. John Anderson
Ray
Rayilyn Brown
Past Director AZNPF
Arizona Chapter National Parkinson Foundation
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