Researchers say they see promising results from the first gene therapy trial for Alzheimer's disease and one the trial's patients believes the experimental treatment slowed down her disease. But, as this ScienCentral News video explains, it didn't stop it.
Like the rest of the eighteen million Alzheimer's sufferers worldwide, Lola Crosswhite must battle the disease using everyday tactics — the help of medications, written reminders, and assistance from family members, like her daughter Diana Shaw. However, unlike most Alzheimer's patients, Crosswhite also had access to something extra — an experimental gene therapy that she says delayed her decline from Alzheimer's for two years.
Unfortunately, as predicted by the researchers, the treatment has since begun to wear off and now her memory loss is progressing again.
"Even though I've had it all this time, but then it was better," she says. "Now I'm sliding back. So I'm going down the hill again."
In 2002, Crosswhite was one of eight early-stage Alzheimer's patients to volunteer for risky brain surgery to test the safety of the first gene therapy for Alzheimer's. Researchers led by Mark Tuszynski, a neuroscience professor at the University of California, San Diego, introduced cells that had been genetically modified to make more of a substance called nerve growth factor (NGF) into the patients' brains. These cells were injected into areas of the brain where neurons were dying so that they could act as biological pumps, delivering NGF to the surrounding brain cells.
"The growth factor released by these genetically engineered cells will bathe the other cells in the growth factor, slow down the degeneration and thereby improve, or slow the decline in Alzheimer's disease," says Tuszynski. Growth factors are proteins present naturally in the brain, but when their levels are artificially elevated, as has been done in many animal studies, they have been found to prevent cell death, he explains.
Brain cells image: courtesy of Mark Tuszynski, UC San Diego
The team reported in the journal Nature Medicine that during the two years the gene worked, it successfully slowed the progression of the disease. They determined this by taking PET scans of the volunteers' brains before and after the NGF therapy to measure the metabolic activity in the brain. PET scans provide a picture of where blood is being used in the brain — in other words, how active the brain is. They found that in many of the subjects tested, metabolic activity had increased significantly eight to ten months after the treatment. Since Alzheimer's disease causes a decrease in metabolic activity over time, this was a definite improvement.
They also compared the rate at which at which the patients were declining intellectually before and after undergoing the procedure and they found that the decline was slowed by 49 percent on average.
"Measured on the same scale, the existing drugs have about a five percent effect that lasts three to six months," Tuszynski says. "So that 49 percent compared to five percent would be great if it holds up, and that's a big if."
He says the next trial will use an improved delivery method that should keep the gene working longer. Rather than injecting whole NGF-producing cells into the patients' brains, their new method involves actually genetically modifying brain cells inside the patient by injecting the NGF gene itself, carried by an AAV vector. This vector is a kind of harmless virus (adeno-associated virus) that does not stimulate an immune response and can deliver the genes it is carrying to a specific "safe" location in each cell's genome. Deteriorating brain cells can then recover by producing more of their own NGF from this extra copy of the gene delivered by the vector.
"This is a vector that as far as we know, continues to express the gene product indefinitely and if that's the case, then there is the potential to see greater effect," Tuszynski explains.
In spite of these potential improvements, Tuszynski says this therapy should not be considered a cure. Its goal is to slow the progression of the disease.
"So we won't cure the disease, but again what we hope to do is delay the disease for a significant and meaningful period of time. The chance of doing that will be greater with the next generation vector that we are now testing in the next human clinical trial," he says.
A second Phase I clinical trial to test the safety of the new gene delivery method is underway at Rush Medical Center in Chicago, although Tuszynski says it is too early to say anything about how effective the treatment is.
He adds that plans are underway to begin a phase II trial — to test the therapy's efficacy — in early 2007. Unlike the previous trials, this one will include a control group — only two thirds of the volunteers will actually receive the growth factor gene. About one third of the patients will undergo what's called "sham surgery." None of the patients or doctors will ultimately know who received the actual gene therapy. Without such a trial that includes such a control, it is impossible to say whether the effects Crosswhite perceived were real.
For Crosswhite, the benefits felt very real indeed. "I very definitely felt like it was very well worth it, and I would do it again if they'd let me," she laughs.
Crosswhite's daughter, Diana, says she's grateful for the extra time. Even though the gene therapy is no longer working, she's confident her mother will continue battling Alzheimer's as best as she can. As Diana says, "She's a fighter, she doesn't, she's not going to give an inch or anything. We're going to go out fighting."