An ‘aha’ moment

DENVER—Researchers at the University of Colorado School ofMedicine are seeking funding for a $5 million double-blind clinical trialtargeted toward developing a drug designed to halt the progression ofParkinson's disease, a debilitating neurodegenerative movement disorder causedby a lack of dopamine production in the brain.

The university's clinical trial, slated to start in 2012,will include hundreds of human subjects in the early stages of Parkinson'sdisease, says Dr. Curt Freed, lead researcher in the project. This fall, Freedwill begin in earnest to find a foundation or foundations with deep pockets.

Freed and colleague Wenbo Zhou have been studying theeffects of the drug phenylbutyrate for several years before arriving at their"aha" moment. This occurred when the team discovered that phenylbutyrate turnson a gene, DJ-1, that can protect dopamine neurons in Parkinson's disease. Thisdiscovery led the researchers down a new path.

However, the key is early diagnosis or knowledge of agenetic predisposition to the disease, says Freed.

A study on the effects of phenylbutyrate in mice, thanks toa $75,000 grant from the Michael J. Fox Foundation (MJFF), was followed by astudy on 12 human subjects.

Freed says they will go to the MJFF with hat in hand in thefall to apply for additional funding, as well as other foundations andagencies.

"Money has to come from somewhere," Freed says. "My labcurrently spends about $40,000 per month without the costs of a major clinicaltrial. I have always had the responsibility for raising all lab support fromwhatever sources I can find."

In the meantime, "we are continuing to do experiments tomake the big grant more compelling," Freed notes. "Before awarding this size ofgrant, funding agencies want to be pretty sure that the double blind clinical trialwill be successful."

Freed's group is the first in the United States to treatParkinson's with gene therapy, transplanting dopamine cells into the brain torelieve symptoms. The procedure can replace the need for drugs, but does notprevent progression of the disease. Freed and his neurosurgical colleague, Dr.Robert Breeze, have done the operation in 61 patients, more than any othergroup in the world.

"If you're stuck with a damaged brain, having the newbrain cells can help," Freed says. "Ideally, it would be great if wecould stop the disease in whatever stage it's in."

Zhou's research on lab mice was published in the Journalof Biological Chemistry.

"We treated transgenic mice that were genetically programmedto get a form of Parkinson's disease," Zhou says. "Without treatment, thesemice show difficulties in movement and cognition as they reach middle age.Brain analysis reveals accumulation of abnormal protein in their nerve cells.When treated with phenylbutyrate in the drinking water before behavioralabnormalities appear, animals do not develop problems with movement andcognition and their brains do not have pathologic protein deposits."

Researchers then did a Phase I safety study ofphenylbutyrate in 12 newly diagnosed Parkinson patients.

"The test was only for six months and was not designed toshow any effect on symptoms," Zhou says. "We found that the drug had nosignificant side effects, making it possible to move forward with testing inpeople. We think that it is possible to stop Parkinson's in its earlieststages. The reason for this optimism is that much of the brain remains normalin Parkinson's disease, unlike many neurodegenerative diseases. We believe thattipping the balance of brain chemistry to an environment that promotes nerve cellsurvival will stop the disease from getting worse."

Developed by a pediatrician at Johns Hopkins University,phenylbutyrate has been used for 30 years to treat children with a livercondition that prevents them from eliminating ammonia from their bodies, whichultimately leads to death.

Freed discovered that phenylbutyrate may help Parkinson'spatients when he and Zhou were screening a variety of drugs that have thecapacity to activate genes. They found that phenylbutyrate works on DJ-1 in away similar to how steroids act on genes in muscle cells to create muscle bulk.

"If drugs that increase protective genes such as DJ-1 canstop the progression of Parkinson's disease, the treatment of Parkinson's wouldbe revolutionized," Freed stated in a 2009 grant abstract. "Symptoms would notget worse, and patients might never need levodopa or other treatment. In thebest-case scenario, Parkinson's symptoms could be reversed if phenylbutyratecan reverse some of the brain cell damage."

An estimated 1 million people in the United States and 5million worldwide suffer from the symptoms of Parkinson's disease, whichinclude halting speech, a slow and uneven gait and loss of muscular strength.