NEWS

Wiskott-Aldrich Syndrome: Molecular Pieces Slide Into Place

Bob Kuska

When the News last reported on Wiskott-Aldrich Syndrome 3 years ago, the mood among scientists who study this rare condition could be summed up in one sentence: Boy, have we got a lot of work to do. It was a refrain heard throughout science as advances in analyzing DNA helped researchers find scores of disease genes — including the WAS gene in 1994 — with few clues about what the genes actually do in cells.

Like so many other "positionally cloned" genes, the WAS gene looked like nothing scientists had seen before. Database searches came up empty in linking it to a known gene family, a clue sometimes helpful in chasing down a gene's function, and scientists in just 2 years of study already had tallied 115 mutations from patient samples, meaning they would have to characterize the health effects of not one, but many, frequent alterations. As Hans Ochs, M.D., a long-time WAS researcher at the University of Washington School of Medicine, told the News, "Right now, we are feeling our way through. It is like marching through the woods without a trail yet."



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Dr. Hans Ochs

 
Today, Ochs and the growing number of scientists interested in the syndrome say they have succeeded in carving out the initial trails, offering a nice example of how positionally cloned genes are now benefitting people with rare diseases. Though the scientists still cannot distinguish the trees from the forest in many cases, they say their work already has led to vast improvements in diagnosis and earlier treatment, with the first gene therapy studies looming not too far off on the horizon.

Wiskott Who?

First described in the 1930s, WAS is an X-linked (affecting only boys) disorder that, according to most medical dictionaries, must have three symptoms: immunodeficiency, low blood platelet levels, and eczema.

Boys born with the syndrome often have chronic bouts of autoimmune disease, infections, and bleeding. Though patients now live longer than a generation ago, most survive on average only to age 11, often succumbing to a serious infection. For those who live into early adulthood, studies show that the risk of cancer, particularly non-Hodgkin's lymphoma, is high, though the exact risk remains unclear. Current estimates are that about 500 Americans now have the syndrome.

If a suitable donor is available, some boys can be cured with a bone marrow transplant, which reconstitutes the immune system. But, according to David Nelson, M.D., a scientist at the National Cancer Institute in Bethesda, Md., that can be a pretty big "if" in today's world. "In a family, you have a one in four chance on a statistical basis of having a match," he said. "Well, a lot of people are not having four kids anymore."



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Dr. David Nelson

 
Nelson noted that even more problematic is diagnosis. Though WAS has a standard, three-symptom definition in medical textbooks, researchers have long suspected that the story may not be so cut and dry. For example, some boys might have entered the clinic with low blood platelet levels indicative of the syndrome, but eczema or immunodeficiency might be mild or nonexistent. Such scenarios, according to Nelson, have left many a pediatric immunologist mumbling over the years, "Is this Wiskott-Aldrich?"

Some also worried about mistakenly diagnosing less severe conditions, such as immune thrombocytopenic purpura, as WAS. "You don't want to give a bone marrow transplant to a patient who has [this condition]," said Ochs, because it often resolves itself or can be dealt with by removing the spleen.

The WAS gene has changed everything. By noting the often divergent clinical courses of siblings who inherit the same exact gene mutation, scientists have established that WAS is actually a broad spectrum of disease, in which patients may have all the standard symptoms but in varying degrees of severity. "We now have a scoring system," said Ochs. "We can identify the classic WAS at one end of the spectrum and, at the other end, we can identify what is called X-linked thrombocytopenia [low blood platelet levels], which is also WAS in most instances."

But Ochs and others have taken the work another step further. They have published data over the past 3 years showing that different types of gene mutations correlate with different clinical phenotypes. "By looking at large groups of patients and their phenotypes, we can almost predict in the newborn what kind of diseases it will have, based on the mutational analysis," said Ochs.

The push to improve the diagnosis also has provided a boost for treatment. In the hands of an experienced clinician, parents now can get a definitive, gene-based diagnosis very early in a child's life, an important issue in bone marrow transplantation. Experts say that the health risks associated with a bone marrow transplant increase between age 5 and 8.

For couples worried about passing on an altered WAS gene to a child, prenatal diagnosis is also possible. The advantage of this approach is the newborn can receive bone marrow or cord-blood stem cell transplantation as early as possible to cure the disease, a development that was simply not imaginable in the pre-gene days of the early 1990s.

Beating the Odds

Three years ago, few could have predicted so much progress so fast. The field, long dominated by pediatric immunologists, was in the midst of shifting gears from searching for a disease gene to embarking on the scientifically-tall task of determining how the WAS gene and its protein product worked and, when altered, triggered this complex syndrome. As Jonathan Derry, Ph.D., a scientist at Immunex Corp. in Seattle, told the News in 1996, "You go after the gene, you fight to get it, you get it in the end — then it looks like nothing on earth. Then, you say, ‘Where are we?' "

Many wondered whether the field could quickly build the needed research infrastructure, including animal models and a patient registry, to properly study the gene. And, even if it did, could it attract a critical mass of skilled molecular biologists and other basic scientists to solve the molecular puzzle underlying the syndrome?

It seemed like an unlikely proposition. Funding levels had crept along for decades at bare-bone levels. And, in this era when new and interesting disease genes enter the medical literature almost weekly, this hyphenated syndrome that often elicited the comment "Wiskott Who," faced a tough sell in peer review.

But something funny happened along the road to failure: Much of the infrastructure got built, and basic scientists, most of whom had never heard of the syndrome, got interested in the protein produced by the WAS gene.

Scientists say kudos should go to the grassroots efforts of the Immune Deficiency Foundation in Towson, Md., and the new Jeffrey Modell Foundation of New York, N.Y., which has helped to increase public awareness of primary immune deficiency diseases and, in partnership with the National Institutes of Health, is supporting several new research grants in this area.

The Maryland foundation, in particular, has helped to expand the research infrastructure. In 1997, it launched the first WAS patient registry, one of eight primary immune deficiency registries now up and running. According to K.K. Marino, director of IDF medical registries, the WAS registry currently has approximately 175 patients registered. All eight registries are funded by NIH through a grant to the IDF.

Jerry Winkelstein, M.D., who runs the registries for IDF at Johns Hopkins University in Baltimore, said the goals of the WAS registry include establishing a more accurate portrayal of WAS incidence in the United States and developing a clearer clinical picture of the syndrome and its many shades of disease.

In addition, the IDF supports a molecular genetic diagnostic service at Ochs' laboratory in Seattle. Now into its second year, the laboratory has helped to meet genetic testing needs among families with histories of a primary immune deficiency, including WAS. Experts say private industry has shown little interest in developing genetic tests for small-market rare diseases, leaving many patients with nowhere to turn for testing throughout much of the 1990s.

Does It Sting?

Scientists also note that, in many ways, research on WAS has moved forward on its own scientific merits. The reason is found in its protein product, which goes by the pesky acronym, WASP. Like its insect name, it has created considerable buzz among scientists interested in the cytoskeleton, signal transduction, and programmed cell death.

Though WASP is expressed in lymphocytes only, many basic scientists have gone swatting after the protein because its function seems to be unique in the biology of the cell. "A lot more people are working on Wiskott than most other rare diseases because of what the protein does," said Katherine Siminovitch, M.D., a scientist at Mount Sinai Hospital in Toronto, who has also helped to develop a mouse model for the disease. "It is an extremely interesting protein from the biologist's point of view."

Simonovitch explained that like a railroad switch, WASP appears to connect signals to two different tracks of cell behavior. First, it helps to relay signals into the nucleus, allowing the cell to respond to changes in its environment. Secondly, WASP triggers the cytoskeleton to undergo structural changes in response to the signal. Scientists say no other known protein has this duel role of influencing the nucleus and the cell structure.

Interestingly, researchers have identified a close cousin of the WAS protein, known as N-WASP. Unlike the protein in lymphocytes, N-WASP is found in virtually all human cells. This has led at least two large laboratories to embark on studies to compare both proteins, hoping that the lessons learned will be valuable in more ways than one.

"I am a cancer researcher," said Tadaomi Takenawa, Ph.D., a scientist at the University of Tokyo, whose group isolated N-WASP 3 years ago in neural cells. "So, I hope that clarifying the functions of the WASP family of proteins gives us clues to cure not only Wiskott-Aldrich, but also to prevent the movement, invasion, and metastasis of tumor cells."

Looking Ahead

What will the future bear for the Wiskott-Aldrich syndrome? According to Ochs, the field will continue enjoying "the symbiosis between patient care and basic science." On the clinical horizon, researchers say gene therapy needs to move forward. Many point to the emerging technique of DNA repair, rather than full gene replacement, as a good bet for the first gene therapy experiments.

In fact, R. Michael Blaese, M.D., a former NIH scientist who has studied WAS for over 30 years, recently moved to the Kimeragen Corp. in Newtown, Pa., to coax this approach forward.

"I would like to see us develop a definitive strategy for treatment," said Nelson, who is interested in DNA repair studies, in collaboration with Blaese and colleagues at NIH.

"Whether that is a more effective [BMT] regimen, gene therapy, gene correction, or whatever, I would like to see us come up with a way that we can cure these kids and relieve all of the suffering that they go through."

Ochs said he remains encouraged that the job will get done. "I think we are moving at a very rapid pace," he said. "If you consider that 5 years ago, nobody knew what the protein was doing, and we were just trying to make antibodies to identify it. Now, however, we are really on the molecular level and have a lot of the pieces."



             
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