Alzheimer’s patient is taking her chances in clinical trial
Gloria Lucio had two pencil-sized holes drilled into her skull in April, part of a procedure to possibly combat her Alzheimer’s disease.
The surgeon may have injected an experimental gene therapy drug deep into her brain. Or, after months of tests, consultations and preparation, the Pasadena woman may not have received any treatment at all.
The willingness to endure such a surgery for a clinical trial with no guarantee of treatment seems extraordinary. But Lucio and her husband, Don Jones, acknowledge a biting reality: Even if she did get the drug, it may not work.
The substance that may have been injected — a virus carrying genes intended to produce a chemical called nerve growth factor — looked promising in a preliminary trial, but so have many other now-failed treatments.
Such are the options for someone with Alzheimer’s disease in 2010.
The Alzheimer’s Assn. recently estimated that cases of the neurological disease, which now affects about 5 million Americans, will more than double in the next 40 years — at enormous personal, social and economic costs.
The report was the latest in a drumbeat of dismal news about Alzheimer’s. In March, a Phase 3 clinical trial of the promising drug Dimebon failed to produce positive results — another highly anticipated experiment gone bust. Medications currently in use can only mitigate early symptoms; none have been found to slow the disease.
“There’s a feeling of desperation, not only among people with Alzheimer’s disease or mild cognitive impairment but also with their family caregivers,” said Gail Hunt, president of the National Alliance for Caregiving.
But behind the gloomy headlines, researchers say they know more about the cunning illness than ever before. They’re developing techniques to identify it in its earliest stages, and within the next decade they expect treatments to slow or forestall the disease.
Given the swelling numbers of those afflicted, any advance can’t come too soon.
“I want to get well,” Lucio said on a rainy morning, a few days before her April surgery. “I want my brain to be healthy. But I’m scared. The holes — how big will they be?”
Her son, Valentin, 18, was sitting nearby. He points to the tip of his pinkie finger. “The holes are this big, Mom.”
She nodded, still worried.
Lucio was reluctant to undergo the experimental treatment but, with a clear understanding of the situation, felt she had no choice. The disease had been making steady advances for years, quietly stealing pieces of her identity.
A former nurse-practitioner and political activist, she was afflicted with Alzheimer’s at an earlier age than most patients. Lucio is homebound now and no longer fixes meals or pays bills. Her short-term memory is a sieve, and her husband and son don’t leave her alone for long.
“How old are you?” she is asked.
“Sixty-eight,” she said, somewhat hesitantly.
She is 57.
“How big are the holes?” she asked again.
Valentin crossed the room and gently touched the sides of his mother’s head with his fingers as rain pounded on the picture window next to her chair.
“They’ll be this size, Mom. They’ll be right here.”
Scientific developments
The predominant theory for the cause of Alzheimer’s is a buildup of two types of proteins in the brain: beta-amyloid and tau. Scientists believe that plaques of beta-amyloid (which accumulate between nerve cells) and tangles of tau (which build up inside nerve cells) block the cells’ ability to communicate and ultimately destroy them.
But the disease process is now thought to begin far earlier than anyone suspected — as long as 15 years before symptoms appear. In a study published in December in the Archives of Neurology, researchers found amyloid deposits in the brains of people who had no symptoms of dementia but later developed Alzheimer’s.
Such knowledge is changing efforts to fight the disease.
“I think that the impact of the treatments is likely to be greater if we use them earlier,” said Dr. Paul Aisen, director of the Alzheimer’s Disease Cooperative Study at UC San Diego. “For disease-modifying treatments, a late stage may be too late to benefit.”
Until recently, plaques could be verified only during an autopsy, so Alzheimer’s diagnosis is based on highly subjective paper-and-pencil memory tests. That could change.
Biomarkers — physical signs of the disease — have been identified and are expected to soon replace memory tests. One detection method uses a PET scan with a radioactive chemical to detect beta-amyloid in the brain. Another measures tau and beta-amyloid proteins in spinal fluid.
Diagnosing and intervening earlier in the disease process, scientists predict, will bring about treatment successes.
Bristol-Myers Squibb is testing a compound, gamma secretase inhibitor, that could slow progression of the disease in people with mild cognitive impairment, considered a precursor to Alzheimer’s. The study of gamma secretase inhibitor, an enzyme that appears to slow or stop the buildup of amyloid plaques, is in the very early stages, but other companies are planning early-stage clinical trials as well.
Though the emphasis has shifted to early treatment, researchers also are employing innovative, even risky, strategies on patients whose Alzheimer’s is more advanced.
Among the 175 Alzheimer’s medications in development are ones that could combat the buildup of tau tangles and others that could help protect neurons, such as the nerve-growth factor study Lucio opted to try.
Under the knife
Lucio checked into UCLA Medical Center on April 15, looking pale and worried. The night before, the family had discussed her options over a dinner of cheeseburgers, salad and corn. She almost canceled the surgery. “If you want to back out, you can,” her husband had told her. “But if we didn’t do this, what would be the other choice?”
During the procedure, her neurosurgeon, Dr. Antonio De Salles, attached a frame to her skull that would enable a portable CT scan to calculate the exact part of the brain for the injection. He then began burrowing two holes — stopping to open a sealed document that instructed him whether to administer the nerve growth factor.
He then may have cut into the dura mater, the tough tissue that envelops the brain, and injected the gene therapy drug into a region called the nucleus basalis of Meynert; there, Alzheimer’s destroys neurons important to short-term memory and other cognitive functions.
As for the nerve growth factor itself, the substance controls the development of nerve cells throughout the body. It is also thought to work as a nutrient to protect brain cells that typically die off because of Alzheimer’s disease. Getting nerve growth factor into the brain, however, is difficult, and researchers have done it only by delivering genes that make it directly into the brain.
“The study represents how far science has come,” says Joshua Grill, a neuroscientist and the investigator conducting the UCLA arm of the study. “We’re no longer throwing spaghetti at the wall to see what will stick. We’re targeting things. We’re going after what we know is happening with the disease.”
Looking ahead
If researchers are discouraged by the slow rate of progress in combating Alzheimer’s, they won’t say it.
“We think we’re very much on the right track,” Aisen said. “We believe we understand what drives the process and have candidates that address it. We have tools to measure disease more accurately and identify people at the earliest stages. That said, we’re not finished getting past some hurdles.”
But they feel the press of time. More than half a million cases of the disease are diagnosed each year.
“These are frightening numbers, and people should be very worried,” said Dr. Debra Cherry, executive vice president of the Alzheimer’s Assn., California Southland chapter. “We would all like research to go faster — especially if you are someone who is living with the disease.”
Lucio is more upbeat. On a sunny June morning, she and her husband are looking ahead.
“I’m absolutely sure she received the treatment,” Jones says. “Gloria is doing so much better. She’s engaging in conversation. She’s relaying messages to us. I came home one day, and she was making her own lunch.”
The researchers warn against any expectations. And, until the two-year study is completed, they cannot be sure whether Lucio received the treatment. But for now, participating in the trial has given the Jones-Lucio family a sense of optimism.
The family is making plans for the first time in two years. They hope to attend a family reunion in Texas, and Valentin soon will begin looking at colleges.
“Hope is what has come out of this process,” Jones said. “Before, we didn’t have any.”
