ScienceDaily (Mar. 24, 2009) — GAINESVILLE, Fla. — A growth factor used in 
clinical experiments to rescue dying brain cells in Parkinson patients may 
cause unwanted weight loss if delivered to specific areas of the brain, 
according to University of Florida researchers in the March online edition of 
Molecular Therapy. 

The discovery is a cautionary warning for experimental treatments to treat 
Parkinson's disease that use GDNF, short for glial cell line-derived 
neurotrophic factor.
In addition, the finding broadens understanding of the brain's role in the 
regulation of metabolism and body weight, suggesting that gene therapy 
techniques in the brain potentially could control obesity.
"People shouldn't interpret our result to mean this is a terrible side effect 
that precludes ability to do GDNF gene therapy for Parkinson's disease, but it 
does show that it is extremely important to place the therapy in the correct 
brain region," said Ron Mandel, a professor of neuroscience at UF's McKnight 
Brain Institute and the Powell Gene Therapy Center. "The good news for 
Parkinson's patients is that the finding doesn't discredit the current 
target."
Parkinson's disease affects between 500,000 and 1.5 million Americans, causing 
patients to gradually develop movement problems, including tremors, stiffness 
and slowness of movement.
Current treatments only address symptoms and do nothing to slow the disease's 
progression, which is caused by degeneration and death of nerve cells that 
produce dopamine, a substance necessary for communication between cells that 
coordinate movement.
GDNF rescues the dopamine-producing cells in cell cultures and animal models 
of Parkinson's disease.
But Parkinson patients were disappointed in September 2004 when the 
biotechnology company Amgen discontinued a clinical trial using GDNF because 
of concerns about safety and effectiveness. The therapy was delivered through 
surgically implanted catheters to a region called the putamen, and several 
patients said their physical conditions and quality of life improved.
A different approach in a more recent trial by the biopharmaceutical company 
Ceregene involved gene therapy, in which the gene to produce neurturin, a 
sister protein to GDNF, was transferred into the putamen region of Parkinson 
patients. But it showed no marked effectiveness.
In a clinical trial where GDNF was delivered to the fluid-filled spaces of the 
brain, a common side effect was weight loss beyond what could be attributed to 
surgery, diet changes and energy expenditure.
Based on these results UF researchers looked for areas in the brain that might 
be responsible for weight loss. The UF researchers noticed that GDNF delivery 
to the area of the brain known to control weight and general metabolism 
reduced weight gain in younger rats and caused significant weight loss in 
older ones.
In the current study, UF scientists compared weight loss in obese rats when 
two distinct brain targets received therapy using an adeno-associated virus to 
deliver the GDNF gene.
When GDNF flooded a bundle of nerves known as the nigrostriatal tract, a 
potential target for Parkinson therapy, the obese rats lost a great deal of 
weight — about 80 grams. But when GDNF protein was overexpressed in a 
different therapeutic target, the hypothalamus, weight loss was only about 
half as much. In both locations, there was a steady decrease in body weight 
throughout the experiment that could only partially be explained by food 
intake.
"These are interesting findings that enhance our understanding of how the 
dopamine system interacts with obesity," said Dr. Ole Isacson, a professor of 
neurology at Harvard Medical School and director of the Center for 
Neuroregeneration Research at McLean Hospital who did not participate in the 
study. "An interesting corollary is that overexpression of GDNF may act on 
satiation or appetite reduction — clearly this is a unique angle for using 
GDNF, which has only been applied for neuroprotection for Parkinson's disease 
or motor neuron disease."
The discovery also suggests that direct injections of GDNF therapy to certain 
brain regions are not advisable because patients could lose unhealthy amounts 
of weight.
"It is a fascinating discovery as a future potential treatment for weight 
loss, and for Parkinson's treatment, it means it is important to watch 
patients' weight and metabolism carefully," said Dr. Pedro Lowenstein, 
director of the Gene Therapeutics Research Institute at Cedars-Sinai Medical 
Center who was not involved in the research. "It is also interesting because 
there is a propensity for Parkinson patients to get depressed, and it is not 
very clear why. This study found a link between GDNF and CRH neurons — cells 
that are involved in mood regulation. That is very intriguing."
Meanwhile, researchers studying potential obesity therapies that work by 
influencing how the brain regulates energy use and food intake now have much 
more to consider.
"The results show for the first time that GDNF overexpression in an anatomical 
area in the brain known as the nigrostriatal tract is involved in metabolism," 
Mandel said. "For people who study metabolism in the brain, this sheds some 
new light on the playing field. But it shows the playing field is more 
complicated that anyone dreamed." 
### 
The work was supported by the National Institute of Neurological Disorders and 
Stroke and by the Medical Research Service of the Department of Veterans 
Affairs. 

Adapted from materials provided by University of Florida.

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