Three out of five elderly Parkinson's disease patients recovered sexual function after a year-long Phase I clinical trial testing a novel form of brain therapy. Two of the three also enjoyed revival of taste and smell - frequent casualties of PD.

More to the point, all five patients experienced improved motor skills after 12 to 18 months on pump-driven injections to the brain of a human nerve growth factor called GDNF, or glial cell line-derived neurotrophic factor. GDNF also lessened the tremors caused by L-dopa, the commonest drug used to treat the disease's progressive depletion of dopamine.

Parkinson's disease afflicts up to 1.5 million Americans a year. Its main feature is loss of dopamine neurons in the brain. Unlike surgical treatments, GDNF seems to protect the remaining healthy dopamine-secreting neurons of the vital protein.

Nature Medicine, released online March 31, 2003, carries an article titled "Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease." Its lead author is neuroscientist Clive Svendsen at the Waisman Center Stem Cell Research Program, University of Wisconsin-Madison.

"This study," Svendsen told BioWorld Today, "induced a remarkable uptick in the motor skills of the five Parkinson's patients in advanced stages of their disease. It also restored the ability of their brains to store dopamine, a key neurotransmitter that helps the brain control PD's impaired muscle movements. PD is a chronic, progressive and ultimately fatal disease. It's marked by uncontrollable shaking and an inability of the brain to command muscles to move in a programmed manner.

"The tests that were done," the journal article noted, "showed reductions in many of the rating scores for PD. This study," it cautioned, "warrants careful examination of GDNF as a treatment for Parkinson's disease."

"This is the first paper to show that a growth factor administered to the brain has any physiological effects on humans," Svendsen observed. "Our main concern," he added, "was the safety issue. It's important to keep in mind the limited scope of this Phase I trial, but the clinical results we observed were impressive."

Recombinant Nerve Growth Factor From Amgen

The clinical trial was carried out at the Frenchay Hospital's Institute of Neurosciences in Bristol, UK. It was coordinated by neurosurgeon Steven Gill and neurologist Peter Heywood. "It raises hope," Svendsen said, "that GDNF, which has long been studied in rats and primates, may one day become a new therapy for alleviating the symptoms of Parkinson's sufferers. GDNF is known to protect dopamine neurons from cell death," he continued. "We know from rat models that the molecule has strong positive effects on dopamine neurons. It can make them produce new processes, and function better. GDNF is like plant food; it makes cells healthier. In moving from an animal model to a human, there is substantial increase in the volume of tissue through which this relatively large protein must penetrate.

"In this Phase I trial, we delivered GDNF directly into the putamen of enrolled patients with PD," Svendsen recounted. "Recombinant-methionyl human GDNF was prepared for us by Amgen [Inc., of Thousand Oaks, Calif.]. It was cloned in Escherichia coli host cells that contain an expression plasmid with a DNA insert encoding mature human GDNF.

"The protein was administered directly to the brains of the five patients - aged 62, 46, 56, 56 and 51 - through an indwelling catheter," Svendsen explained. "Every day for 18 months, pumps pushed up to 40 micrograms of GDNF into a region of the brain known as the putamen. There it was absorbed by cells near the tip of the catheter and, we suspect, was drawn deeper into the brain where the dopamine-producing cells reside. The overall result in those patients was an improvement in their clinical symptoms and daily quality of life. After one year, they exhibited no serious clinical side effects. The treatment also reduced dyskinesias, the involuntary, jerky muscle movements associated with the L-dopa drug treatment - by 64 percent.

"In assessing the GDNF drug's effects on patients," Svendsen went on, "tests administered to measure motor skills showed a 39 percent improvement. Those that measured daily living activities reflected a 61 percent betterment. The only consistent finding," Svendsen recalled, "was Lhermitte's phenomenon - a tingling passing from the neck down the arms and legs, provoked by neck flexions. This event was mild, nondistressing and often described as pleasurable.'"

"In all patients," the Nature Medicine paper recorded, "the symptoms of Parkinson's disease improved after three months of GNDF infusion. Periods of severe immobility - one of the cardinal features of PD - that occupied approximately 20 percent of the waking day before surgery, were eliminated completely after six months of GDNF infusion."

Underscoring improved muscle control, positron emission tomography (PET scans) performed by David Brooks and Gary Hotton at London's Hammersmith Hospital showed a significant increase in the brain's ability to store dopamine. That suggests a distinct effect of GDNF to help dopamine do its job of controlling the body's muscle movement - impaired by PD.

Either Way, More Dopamine, But Approach Limited

"What we're seeing," Svendsen commented, "is that GDNF either up-regulated dopamine metabolism, or it has inspired sprouting of nerve cells. Either way, you've got more dopamine, which is good news."

He emphasized the limited scope of the preliminary Phase I trial, and the fact that it was not a double-blind, placebo-controlled study. "The limitation of the trial's approach," he pointed out, "is that a pump and catheter were needed to administer the growth factor. But the work advances the possibility of using genetically modified neural stem cells implanted in the brain to produce GDNF. It might be an ideal molecule. The key thing that we know now is that it's safe. But I'm confident in the clinical results," he said, "which argue for a more comprehensive clinical trial with a larger number of PD patients. Such a trial," Svendsen allowed, "is planned for the near future.

"Finally," he concluded, "the planned trial may stimulate further related studies in other neurodegenerative diseases, such as Alzheimer's, Huntington's and ALS [amyotrophic lateral sclerosis] in which various neurotrophic factors have also been shown to have beneficial effects in animal models."