Maryland Youth May Help Pioneer Cure for Gaucher’s Disease
Brian Berman, age 3, was 33 inches tall and 25 inches around. His belly was so swollen that his mother said he looked like a cabbage with legs.
Brian was a loser in the genetic lottery, the game every person-to-be plays at conception.
Because he descends from Eastern European Jews, the odds were 1 in 676 that he would be born with an obscure illness called Gaucher’s disease. But because his parents both carried one recessive gene for this disease, the odds were 1 in 4 that he would get it.
And he did. Like 15,000 to 20,000 other Americans, he inherited two bad versions of a gene that helps oversee one of the body’s arcane housekeeping chores, cleaning up worn-out blood cells.
In another way, however, he was unusually lucky. Brian happened to be a patient at the federal government’s health research complex in nearby Bethesda at just the right moment. Researchers working there under Dr. Roscoe O. Brady had been trying for 30 years to isolate, purify and modify the enzyme that his body lacked. After several false starts, they hoped they had hit at last upon the right formula.
On Dec. 22, 1983, just three weeks before he was scheduled to have his spleen removed, Brian received an injection of modified glucocerebrosidase. It worked. Or so it appeared.
Energetic Third-Grader
Now, at age 7, Brian still gets the shots every Thursday, and he still shows some signs of the disease. His belly is a bit larger than normal. But he is clearly a happy, bright, energetic third-grader.
He is also a sort of medical pioneer, for he is the only person to receive regular therapy with what, some experts believe, will prove to be the first successful treatment for Gaucher’s disease.
Other researchers are not so sure. They point out that Brian is the only patient who has clearly benefited from the treatment, and it has failed in several others.
But to Brian’s mother, Robin, herself a physician, the meaning is clear: “I feel it’s a miracle.”
To Brady, the boy’s improvement--and the potential it may hold for others--are the rewards of a career largely spent studying one rare disease.
“It certainly is gratifying,” he says. “It took a long time, didn’t it? This started in 1957. Thirty years.”
The ordeal for Brian and his parents began in the spring of 1983 when Mrs. Berman glanced at her son while he was napping.
“I noticed that Brian’s belly looked very big to me,” she remembers. She had already brought this up with to two other doctors, who assured her nothing was wrong. This time, though, she asked a surgeon who lived nearby to examine her boy. “He said, ‘There’s a big mass in there.”’
His spleen was enlarged. At first, doctors suspected leukemia. But finally the diagnosis came back: Gaucher’s disease.
“I frantically racked my mind,” Mrs. Berman said. “We had about 10 minutes on it in medical school. I couldn’t remember what it was all about.”
She quickly learned that some of the world’s experts were down the road at the National Institute of Neurological and Communicative Disorders and Stroke, where Brady is chief of the Developmental and Metabolic Neurology Branch.
She approached Dr. John A. Barranger, then the clinical director in Brady’s group. “I asked him if he would let me work gratis. I didn’t want to be paid. I wanted to learn everything I could about this disease.” She closed her family practice and began seeing Gaucher’s patients.
Lipid Storage Disorders
She learned that Gaucher’s disease is one of a handful of so-called lipid storage disorders, including Tay-Sachs disease, that are most common among Ashkenazi Jews, those who emigrated from Eastern Europe.
When blood cells wear out, the body recycles them by breaking down their building materials, including a fatty substance called glucocerebroside. To do this, it makes a specialized enzyme called glucocerebrosidase. However, in Gaucher’s victims, the gene that makes this enzyme is defective. As a result, glucocerebroside builds up in their bodies.
It tends to collect in cells called macrophages in the liver, bone marrow and spleen. The consequences vary greatly from person to person. Some die in childhood, while others notice no symptoms until late in life.
Often though, they become severely anemic. Their blood doesn’t clot properly, so they bleed at the slightest injury. Their livers and spleens are enlarged. Over time, their bones grow brittle and break easily. They may suffer deep bone pain.
Removing the spleen can help temporarily. But this may also increase susceptibility to infections, and some think it speeds bone damage. Otherwise, little can be done to control the disease.
During that fall, there was “an aura of expectation” in Brady’s lab as researchers worked on the enzyme, Mrs. Berman remembers. But meanwhile, Brian’s condition quickly worsened.
“He started to get very sick,” she said. “He went down hill so that he couldn’t walk up stairs. He looked like a cabbage with legs. He had a huge belly and wasting extremities.”
He was extremely anemic. His heart raced at 130 beats an hour, trying to pump enough oxygen-poor blood through his body. He also bled easily. His parents could not discipline him, because even a mild spanking would bring spots of blood to his skin.
When doctors at the institute offered to give Brian their latest version of a replacement enzyme, the choice for the Bermans was easy.
“The first week, his blood count went up a little bit,” Mrs. Berman says. “Everyone was encouraged. The second week, it went up again. We were walking around on a cloud. We canceled his surgery. We clearly felt we were witnessing a miracle.”
After seven weeks of progress, however, the lab ran into problems making the enzyme. For seven more weeks, he got no shots.
An Unbelievable Time
“He went right back to ground zero,” she said. “We were thrilled and yet beside ourselves. It was an unbelievable time. Then he got it again, and his blood count went back up.”
This happened twice more, and each time his hemoglobin levels fell after dramatic climbs. Now his hemoglobin is normal.
While laboratory tests showed improvements, the benefits of the treatment were clear to anyone who saw Brian. Gradually he regained the energy of a normal little boy, running and jumping with his friends. Now he is 44 inches tall, and his waist is 22 inches. While still small for his age, his growth has begun to speed up.
What Brian seems to remember best about his sickness is the taunts of other children. “They used to call me fatso,” he says.
For Brady, Brian’s improvement is one happy step in a long, often slow struggle against Gaucher’s disease. When he began working on the disease, no one knew what caused it. In 1959, he put forth the theory that victims lacked an enzyme, and he finally proved this in 1964.
Next, he and his co-workers developed ways to diagnose the disease, identify carriers who might pass it on and check fetuses for the disease before birth.
“When these became available, we began to think about what we could do for these patients,” he says. “Do they respond to exogenous (outside) enzymes? We had no reason to suspect that they would or would not.”
By 1974, he had purified a little of the enzyme. Although there were signs that it would do some good, it was simply too hard to obtain to be practical. He and his colleagues spent two more years developing another purification procedure. This time they got sufficient quantities of the enzyme by painstakingly separating it from placentas.
But instead of going to the cells that were filled with glucocerebroside, the enzyme was gobbled up by other body tissue. After five years of testing, it was clear that the purified enzyme would not work. So the scientists began tinkering again. This time, they stripped off some of the sugar that makes up the enzyme.
Rebuilt this way, the enzyme seems to zero in on the swollen cells. It was given initially to seven patients, but only Brian responded. Brady believes it failed in the others because they did not get big enough doses.
To others, however, this suggests that the enzyme is not the answer to Gaucher’s disease.
Brian’s improvement is encouraging, says Dr. Edward I. Ginns, a Gaucher’s researcher at the National Institute of Mental Health. “But his treatment can’t be generalized” to others. “We don’t completely understand what is going on. There are patients who have a beneficial reaction to something, but it doesn’t help anyone else. I think that was an isolated case.”
Change for the Better
Currently, the researchers are in the midst of a so-called Phase 2 trial with the modified enzyme. Doctors have taken liver biopsies before and after single injections in eight people.
“We see definite changes for the better,” Brady says.
The researchers will perform this experiment on at least 18 people before moving on to the final stage of study. In that phase, they will give repeated doses to about a dozen people. The goal is objective proof that the enzyme changes the course of Gaucher’s disease.
Barranger, who left Bethesda last year in a bitter dispute with Brady, says the treatment is being “hyped” by its supporters.
“I spent 10 years trying to make this approach a therapy for these patients, but from the point of view of a truly reasonable, rational, dependable and reproducible one,” he said. “Up to a year ago, that wasn’t done. It wasn’t clear that this worked.”
Does it work? “The answer is yes,” responds Brady, and he promises to publish the proof.
Among those closely watching this work is Dr. F. Scott Furbish of Genzyme, a Boston biotechnology firm that makes the enzyme in very small quantities solely for the federal studies.
He said it takes about a ton of placentas, obtained from hospitals, to extract enough enzyme for one injection. He predicts that if the treatment is approved by the U.S. Food and Drug Administration, it will cost patients $30,000 annually. That will drop to $12,000 after Genzyme scales up its production.
“What we are proposing for a cost is very, very reasonable, compared to what hospitalization costs for Gaucher’s patients,” he said. Insurance companies “would be delighted to have something that works this cheap.”
Meanwhile, doctors at the federal research institute believe they have found an answer to Gaucher’s disease.
“For the first time in this kind of disease, there is a therapy,” says Dr. Norman Barton, clinical director of the program. “In Brian, there is objective evidence that it works.”
