For the first time, victims of the devastating genetic illness, Gaucher's disease, may be dramatically helped by a new therapy. For the estimated 5,000 to 15,000 Americans who live their lives in pain and fatigue and who may be bedridden for years, there now is genuine hope that the ravages of this sometimes fatal disorder can be almost completely controlled.
Robin Berman, medical director of the National Gaucher Foundation, anticipates that "enzyme replacement will be to Gaucher's what insulin was to diabetes, what Factor VIII clotting factor is to hemophilia." Even the sickest patients will recover eventually, the specialists believe.
Scientists at the National Institutes of Health who have been working on Gaucher's for some 40 years, along with those at a Boston biotechnology firm, believe their Gaucher treatment marks the first time that an enzyme missing in the human body because of a glitch in genetic material has been effectively replaced, fully restoring normal function.
Roscoe O. Brady is the NIH geneticist who identified the cause of Gaucher's disease and subsequently isolated the missing enzyme itself about 30 years ago. A few weeks ago, the outcome of a clinical trial he conducted on 24 patients with Gaucher's, 12 of whom were treated with the modified enzyme, was published in the American Journal of Human Genetics.
All 12 treated patients, ranging from very young children to middle-aged adults, "exhibited striking improvement," the scientists said. "Patients who were incapacitated prior to this treatment have resumed activities such as work and school."
If this is the happy culmination of his life's work for the 66-year-old Brady, it is simply "a miracle," as far as Robin Berman is concerned. Three of Berman's six children have Gaucher's disease and two others are carriers.
Both family practitioner Berman and her businessman husband, Dennis, are carriers of the recessive gene that causes the illness. In this country, about two thirds of the Gaucher patients are descended from Eastern European Jews. In Europe, about half the patients are non-Jews, and in some countries it is found mostly outside the Jewish population.
In the new treatment, the substitute enzyme is derived from human placental material, purified and then modified in a way that lets it zero in on the precise cells that need it.
Enzyme replacement has been tried with only marginal success for such diseases as cystic fibrosis or the disorder in which the missing enzyme is ADA, adenine deaminase.
Earlier work in enzyme replacement for Gaucher's was disappointing. The treatment seemed to work for some patients in some aspects of the disease, but most specialists continued to pin their hopes and their research on gene therapy.
Now, however, the modified enzyme product, called Ceredase, appears to work on all patients to a greater or lesser extent, depending on how long they have been ill and how seriously.
Alison Taunton-Rigby, scientist- spokeswoman for Genzyme, the Boston firm that makes Ceredase, says the enzyme replacement does not cure the disorder -- probably only gene therapy could actually do that. "But," she says, "here is a disease that can be extremely debilitating and life-threatening, and it used to be there was no hope."
Some victims have died soon after the onset of the disease, which can occur at any time after birth and at any age. Others may have no symptoms at all, but many are deformed, in almost constant agony and subject to broken bones for year after year.
There are three types of the disease. In the U.S., Type-1 Gaucher's is the most common genetic disease in the Jewish community, far more common than the always fatal Tay-Sachs disease, for example. Gaucher Types 2 and 3 are found in all racial and ethnic groups and tend to be even more virulent, affecting the central nervous system and producing not only chronic bone and joint problems but retardation and dementia as well.
The current trials have all been done on the more common Type 1, but Brady is readying trials with the more deadly forms of the illness.
In addition to her work with the National Gaucher Foundation, Berman has worked at NIH alongside Brady and his clinical chief, Norman Barton. And the Bermans' son, Brian, was the first Gaucher's patient treated with the modified enzyme.
When he was 6, his spleen was so enlarged he literally looked pregnant. He notes wistfully in a videotape he made for the foundation that "my friends called me fat, but I wasn't."
He has been on the enzyme now for almost six years. Recently, his dose was reduced drastically, but he continues to improve. Today at 11, he looks like a normal healthy kid.
Gaucher's disease is caused by the body's inability to dispose of lipids, fatty substances that are normally broken down by the missing enzyme. As a result, they accumulate in the bone marrow, the liver and the spleen, preventing these amd other organs from functioning properly.
The spleen becomes enlarged and blood platelet counts plummet; the accumulating lipids crowd out red blood cells produced by the bone marrow so that the victim becomes anemic. Bones become honeycombed and fragile, deformed and subject to constant breaks and barely functional.
For New Orleans publicist Louise Glicksman, mother of two Gaucher patients, a son and a daughter, ages 20 and 16 respectively, the success of Ceredase may be a mixed blessing. Producing it is a complicated and extremely labor-intensive procedure, making it so expensive that in some severe cases it may cost up to $200,000 to bring a patient under control.
The Gaucher Foundation, of which Glicksman is a founding member, is working with health insurance carriers, as is Genzyme, and there has been some success in getting the treatment covered, even on pre-approval experimental programs.
The product has been granted orphan drug status, giving the manufacturers a temporary monopoly in exchange for a guarantee that drugs for limited patient populations will be available.
The foundation expects that the cost will come down eventually. First, when the drug is approved, there will be a larger pool of patients over which the basic costs can be spread. Second, initial treatments were done with relatively high doses, because the sickest patients were treated first. Bigger doses are needed to correct symptoms that have developed in some cases for 20 years or more.
As many as 50 patients around the country are currently being treated, and all are responding, the researchers said. The Food and Drug Administration, which has already granted approval for the drug's use in experimental programs, is expected to approve it for general use sometime before the end of the year. An FDA advisory committee will look at it next month.
Once the symptoms are under control, the researchers expect that the doses may be dropped to as little as one tenth of the initial intensive therapy.
"That," says Brady, "is our next order of business," to find the lowest effective maintenance dose and the lowest dose at which the drug becomes effective, as well as determining if the therapy will work on the other two types of the disorder.
And Genzyme is already starting a program to try to replace the enzyme missing in people with cystic fibrosis. The cure for these diseases must await gene therapy, but control via enzyme replacement may now be at hand.
Brady, whose sense of excitement is almost palpable when he talks about the trials, is being asked by colleagues and friends how it feels to have success so close in his efforts. "How does it feel?" he repeats. "Well, it feels a lot better than if it didn't work, I'll tell you."