By David N. Leff

Back in the early 1990s, a bunch of drug addicts went on a heroin trip - and ended up in the ditch. The synthetic good stuff they bought and binged on turned them into permanent physical zombies - trembling with the shakes, their steps sluggish, their sense of balance erratic, their limbs stiff - their symptoms for all the world like Parkinson's disease (PD).

It turned out that the synthetic heroin was contaminated by a potent neurotoxin called 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine - now much better known as MPTP. The brain cells that drug disrupted were specifically the neurons that make dopamine. And dopamine is the neurotransmitter that keeps bodily movements on a smooth, even keel.

Presumably, those stricken heroin junkies had to switch from their favorite fix to the only drug that treats the symptoms of PD, namely Levo-dopa. This molecule is the precursor of dopamine, which dwindles with advancing age in the dopaminergic neurons that make it. But L-dopa's clinical effectiveness also wanes with time.

Now gene therapy may be coming to the rescue of PD with a neuron-nourishing gene called GDNF. A research paper in today's issue of Science, dated Oct. 27, 2000, bears the title: "Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease." Its principal author is neuroscientist Jeffrey Kordower, director of the Research Center for Brain Repair at Rush-Presbyterian-St. Luke's Medical Center in Chicago.

"Our rationale," Kordower told BioWorld Today, "was that we know from animal studies that GDNF - glial cell-line-derived neurotrophic factor - is a very potent agent for keeping alive these dopaminergic neurons that die in PD.

"There was a clinical trial last year," Kordower said, "which Amgen put on, giving GDNF to PD patients, but they delivered it in the wrong way. So we used a gene therapy method to deliver the trophic factor, and get it to those dying cells. The exciting thing about this approach is that we're trying to alter the underlying course of the disease, attacking the pathological process rather than replacing something that's lost."

That strategy, as reported in Science, involved two in vivo experiments.

Custom Treatments For Aged, Youthful Primates

"In experiment No. 1," Kordower recounted, "we used eight aged monkeys - about 25 years old - which lose dopamine, but don't lose their dopaminergic cells. That mimics some of the earliest cellular features of PD. When a cell begins to degenerate with age, one of the first things it does is shut down its synthesis of dopamine. And six doses of the GDNF gene therapy completely reversed that loss. We were able to bring dopamine levels back from those of an old monkey to a young monkey.

"But aged monkeys don't get symptoms of PD," he said, "so in experiment No. 2 we used 20 young adult monkeys with no PD symptoms. We injected the MPTP neurotoxin up their carotid arteries, to cause parkinsonism. We initiated the parkinsonian state, and then quickly - a week later - intervened with our gene therapy method, based on the GDNF gene. This enabled us not only to prevent the destruction of the dopamine system in the brain, but to prevent the PD symptoms from manifesting."

The co-authors' gene therapy construct featured a viral vector - the vesicular stomatitis lentivirus - containing the synthetic GDNF gene itself, plus a marker gene. That GDNF gene delivery virus, Kordower said, "is modified, it is gutless, so it doesn't have any replicative ability or virulence. This virus enters non-dividing cells. Monkey studies show that about 88 percent of the cells that get transfected are neurons. Once inside the cell, the vector gets into the nucleus, and from there the new GDNF gene expresses its protein. Rodent studies have shown it is safe, very nontoxic, and probably the best vector currently available for long-term gene expression. In a third experiment," he noted, "we found excellent gene expression lasting up to eight months."

As for eventual human trials, Kordower commented that, "One of the things we found in this gene therapy study is that it is an extremely potent approach. Before going on to the clinic, we need to make sure that we can get it under control.

"So one of the things we are doing now is a monkey study, in which we have the vector under tetracycline control. That means if we give the animal tetracycline, we should be able to shut off the GDNF gene. That study is just about to start. Our purpose in running that experiment is that if anything untoward happens when we go in our clinical trials, we will be able to switch the gene off, and so take away the side effects."

Human Clinical Trials Depend On FDA

"Once we clear this one hurdle of controllability," Kordower noted, "we'll be ready to go. The results of that study," he pointed out, "should take six to eight months to complete. Then we will approach the FDA. It's hard to know when we will be able to go into clinical trials because we don't know what the FDA will require of us."

The closest thing to this gene-therapy form of treatment is the ongoing experimental targeted injection of human fetal cells into the brains of PD patients. Kordower, who is also part of such a fetal-cell clinical trial, suggests that "Fetal transplants are more directed toward advanced, late-stage patients, whereas our gene therapy treatment is more toward recently diagnosed individuals."

He said that both stereotactical brain surgery approaches, "can be done under local anesthesia, with a short hospital stay." On this score, he added, "GDNF is an extremely potent trophic factor, and it doesn't just affect dopaminergic neurons. So it's important that we direct the deliveries to the specific regions that we want to have it.

"In this regard, there are some other diseases in which this gene therapy approach could be more globally employed. There is some mention of lysosomal storage diseases, but," he concluded, "I could imagine this approach being used for amyotrophic lateral sclerosis and Huntington's disease as well."

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