Pioneering first gene-therapy attempts to rescue brain cells from Parkinson's

Monday, December 12th 2005, 1:57 pm

By: News On 6

WASHINGTON (AP) _ Mike Castle lay motionless as surgeons drilled two holes into his skull and injected a virus deep into his brain. The virus carries a gene and a tantalizing hope: that just maybe it could stall the Parkinson's disease slowly crippling him.

The Illinois man is among a few dozen patients enrolling in the first attempts at gene therapy for Parkinson's, a milestone in the quest to better treat the degenerative brain disease.

It's a time of mixed excitement and caution: These first three studies are to see if gene therapy is safe to try, not to prove whether it works. Yet studies in monkeys suggest at least one of the approaches has the potential to finally target the underlying disease, not merely tame its symptoms.

``It's this delicate balance between giving (patients) hope but making it clear to them, and to the world, that this is still highly experimental,'' says Dr. William J. Marks Jr. of the University of California, San Francisco, who is leading the most closely watched approach _ using a nerve growth factor to rescue dying brain cells.

``It's a gamble,'' agrees Dr. Leo Verhagen of Chicago's Rush University Medical Center, a co-researcher in the project who treated Castle.

``This is the first trial that, if it works, could slow down the disease's progression,'' he explains.

Yet to stress the experiment's unknowns, he bluntly told Castle, ``We are happy if we don't make you worse.''

Parkinson's disease gradually destroys brain cells that produce dopamine, a chemical crucial for the cellular communication that controls muscle movement. As dopamine levels drop, symptoms increase: tremors in the arms, legs and face; periodically stiff or frozen limbs; slow movement; impaired balance and coordination. It afflicts about 1.5 million Americans.

Standard treatments are to replace lost dopamine with the drug levodopa, and a brain implant to control tremors. Both work for a while, but can't stop the disease's inevitable march.

To do that, scientists have long sought ways to protect remaining dopamine-producing neurons, or nerve cells, and rescue dying ones. A candidate: growth factors, protective proteins naturally found in healthy brains.

In the UCSF and Rush study, the brains of 12 patients are being injected with a harmless virus that carries the gene for one growth factor, called neurturin.

Neurturin is a sister to the better-known growth factor GDNF, an experimental drug believed to be showing promise against Parkinson's until a study infusing it directly into the brain was halted for safety concerns. Moreover, infusions don't allow the growth factor to spread deep enough to reach Parkinson's most crucial brain region, Verhagen says.

Scientists hope gene therapy can get around those issues. Rush neuroscientist Jeffrey Kordower found that monkeys with Parkinson's-like damage significantly improved within three months of receiving growth-factor gene therapy, as injured neurons were rescued. He co-founded California-based Ceregene Inc., which is developing the neurturin gene therapy.

``Gene therapy offers another mechanism in which to get these growth factors into the brain,'' said Diane Murphy, a neurodegenerative disease specialist at the National Institutes of Health. ``That's why people are interested in this, since the infusion methods seem to be problematic.''

Two additional gene-therapy approaches:

_Other UCSF researchers are hoping to lengthen the time patients can benefit from Parkinson's medication, through gene therapy designed to spur production of an enzyme that converts levodopa into dopamine. Three patients so far have received a gene-bearing virus, with 12 more to be enrolled.

_And Neurologix Inc. recently announced promising preliminary results from 12 patients who tested an attempt to calm overactive brain activity involved with abnormal movements by boosting production of another neurochemical. The gene therapy seemed safe and, a year later, patients showed some improvement, the company said.

Aside from infection and bleeding as side effects of the brain injections, gene therapy's biggest risk is that it can't be switched off if side effects appear.

But, ``patients are more willing to take risks with something that may help in a more fundamental way,'' notes NIH's Murphy.

That's why Castle, 46, enrolled. Medication controlled his symptoms for over a decade, but he finds it increasingly difficult to walk, with episodes of stumbling and freezing. About two months after undergoing gene therapy, Castle says he notices small improvements in walking, episodes his doctors greet cautiously.

``As far as I was concerned, it was the opportunity of a lifetime,'' Castle says. ``If it works, I'm ecstatic. If it doesn't, I'll be disappointed, but I'll at least know I tried.''