• E-mail
• Print
• Comment
• Font Size
• Digg
• del.icio.us
• Discuss article

Re-Engineering the Diseased Brain

Posted on: Monday, 15 August 2005, 21:00 CDT

Aug. 14--Up to 40 billion viruses will be injected into their brains, they are told, through two holes drilled in the skull. If all goes according to plan, the viral invaders will deliver copies of a repair gene to a small clump of neurons that desperately need help in building new memories.

The experiment at Rush University Medical Center is a bold attempt to slow or halt the volunteers' progressing Alzheimer's disease. If the gene works as designed, it could fix the brain flaws that are robbing the patients of the things that make them who they are -- their intellect and personality.

The gene also could turn out to be a dud and do nothing to help. Or, if it escapes to other parts of the brain, it could cause nasty side effects.

Yet even after being told these things -- and that a primary goal of this study is to determine the safety of genetically re-engineering the brain -- several hundred Alzheimer's patients eagerly sought to volunteer for only six slots.

This is the way science advances: daring and potentially dangerous experimental therapies tested in patients willing to step into the unknown and take the risks.

"They told us it was experimental," said Bob Keller, 72, of Amboy, Ill., whose wife Pat, 64, has Alzheimer's disease. "They were very careful about not saying it's going to help us. Pat said, 'Well, it could help our children or other people.' So she decided she'd like to do it."

None of the patients has experienced any adverse effects from the three-hour surgery or from the billions of new genes in their brains, said Rush neurosurgeon Dr. Roy A.E. Bakay, who performed the procedure. Patients were in a mild or moderate stage of Alzheimer's and deemed competent to understand the risks.

Whether the experiment works won't be known for another year. If it does, advocates say it could become a common therapy for Alzheimer's patients. An estimated 4 million Americans already have the disease, and 360,000 new cases are diagnosed each year.

The study also is a crucial test for the sputtering science of gene therapy, which after 20 years has yet to live up to its promise of providing sweeping cures for many diseases.

Keller already believes the surgery performed six months ago may have pulled his wife of 43 years back from the abyss of Alzheimer's.

"I noticed a difference almost immediately," he said. "Before the surgery, more than half of the time she didn't know who I was. She wouldn't remember. Since the surgery she's almost always remembered. Two weeks ago she did something she hasn't done in years; she made a cake. It was a mix, but she did it herself."

Dr. David Bennett, director of Rush's Alzheimer's disease center, cautions that Pat Keller's response could be a fluke, a psychological boost called a placebo effect, brought on by the surgery itself. Yet when Bennett asks her questions, the answers are heartening:

Bennett: "How's your memory doing?"

Keller: "Better. I remember his name."

Bennett: "Is that important to you?"

Keller: "Yeah, it is."

Bennett: "Are you glad you did it?"

Keller: "Oh, definitely. I would do it again if I had to. My life is different now, better."

Bennett: "In what way?"

Keller: "I remember better, pay more attention."

Jack Edling, 50, of Geneva, another Rush volunteer, at first refused to believe he had Alzheimer's disease. His boss had yanked him off a job in Little Rock, Ark., worried about his memory lapses.

"I said, 'I'm fine. I'm just stressed out like everybody else in a big Fortune 500 company,'" said Edling, who had risen to vice president with the forest products firm Weyerhaeuser. "My boss said, 'There's a ticket at the airport. You're going home and you're going to the hospital.' I said, 'I think you're overreacting.' He said, 'No, I'm not.'"

"He noticed that I was not acting myself," Edling said. "I was not returning phone calls sometimes. I was forgetting a lot of stuff. My co-workers were saying, 'What the hell's wrong with you? Are you OK?'"

Despite his denial, Edling had a feeling that he might be following in the footsteps of his mother, who died at a relatively young age of Alzheimer's.

"I come from some bad genes in terms of Alzheimer's," he said. "My mother and her father and her father's father had this gene that has been passed along through our family."

Now, Edling said, he wants nothing more than to help break the genetic chain that links families to the disease.

"I really wanted to be part of the Rush study," Edling said. "I grew up with my mother. She was almost a corpse when she died. It was horrible."

Edling's motives for participating in an invasive, unproven treatment are typical: If the experimental therapy can't directly help him, at least his effort may help advance knowledge of the disease and pave the way for a future cure.

"These patients are heroes," Bakay said. "They're going out of their way to do something that hopefully will help them, but more likely will help somebody down the line."

The researchers, while expressing caution, hope the Rush findings will match or exceed those of another small study involving the same gene, conducted in California. Researchers there reported in the April issue of the journal Nature Medicine that the progression of Alzheimer's disease in their subjects slowed by about 50 percent for up to two years.

The gene used in the studies generates a chemical called nerve growth factor, or NGF, which is important for brain cells because it helps them survive and grow. Alzheimer's destroys neurons in all parts of the brain that are responsible for higher functions, as well as the cells that make the growth factor, diminishing their power to save other cells in the brain.

Adding NGF genes to a brain with Alzheimer's provides a fresh source of nerve growth factor. The idea is that the relentless weakening and killing of neurons by Alzheimer's disease will be offset by NGF's ability to strengthen the cells and help them survive.

In the study at the University of California at San Diego, researchers inserted the NGF gene into about a million skin cells taken from patients and grown in culture. The skin cells were then placed in an area called the basal forebrain.

What Lola Crosswhite remembers after undergoing the procedure is how the veil of confusion began to lift. Crosswhite, 77, of San Diego, a retired executive, had the operation nearly 3 1/2 years ago.

She said she knew she was going to die of Alzheimer's disease, but she hoped something would be learned from the research that could help her children and her grandchildren. Crosswhite's mother had Alzheimer's and apparently so did her mother's father.

"I probably got more out of the operation than I really expected to," she said. "Afterward I was certainly much better. There's no doubt about it. If they figured they could do it again, I would do it. Without a doubt."

But the problem with using skin cells to deliver the gene is that they appear to die off after a year or two, said UCSD neuroscientist Dr. Mark Tuszynski, a founder of the biotechnology firm Ceregene Inc. in San Diego, which is sponsoring the studies.

For Crosswhite, that means slipping to square one in her struggle to keep new memories.

Trying to overcome that problem, the Rush experiment uses a virus instead of skin cells to carry the NGF gene. The virus, stripped of most of its own genetic material, ferries the NGF gene directly into brain neurons. Incorporated into their DNA, the gene instructs the cells to make nerve growth factor. Monkey studies indicate that the gene supplied by the virus continues to work for more than four years so far with no evidence of turning off.

The Rush experiment is "an absolute technical tour de force," said William Thies, vice president for medical and scientific affairs at the Chicago-based Alzheimer's Association. "The fact that we can take a genetic package, and put it inside somebody's head and have it produce a therapeutic molecule, is a very powerful concept."

Tuszynski said that based on the promising preliminary findings from the California study and the ongoing Rush study, plans are under way to start a larger Phase 2 study later this year or early next year using the Rush technique. That trial will involve 50 to 70 patients with mild Alzheimer's disease, half getting the NGF gene by way of a virus and the other half undergoing a sham operation--which would address the issue of a possible placebo effect.

If the Phase 2 trial shows that gene therapy can significantly slow or halt the destruction of Alzheimer's disease, the procedure could become as common as bypass surgery for heart disease, Tuszynski said.

"If one had this tragic disease and could undergo a one-time procedure to deliver the growth factor into the brain that could have a persistent effect lasting years, which would prevent disease progression or slow progression and significantly improve quality of life, that would be worth it," Tuszynski said.

Bakay agrees, adding that the technique is "really in its infancy. We don't anticipate that this would be a cure by any means. We're trying to delay the disease process. And if you can delay it several years, several decades, then you're much better off than if you're going to be demented in two years and in a nursing home for the rest of your life."

While gene therapy appears promising, other revolutionary treatments for Alzheimer's disease also are under development, Thies said.

"We will have one, two or three therapies that will work in the next 10 years," he said, "but it will depend on people having the courage and selflessness to volunteer for the trials."

-----

To see more of the Chicago Tribune, or to subscribe to the newspaper, go to http://www.chicagotribune.com.

Copyright (c) 2005, Chicago Tribune

Distributed by Knight Ridder/Tribune Business News.

For information on republishing this content, contact us at (800) 661-2511 (U.S.), (213) 237-4914 (worldwide), fax (213) 237-6515, or e-mail reprints@krtinfo.com.

Source: Chicago Tribune

More News in this Category