Meanwhile, Ginsburg, Tsai, and colleagues were following a different strategy to identify the gene encoding the VWF-cleaving enzyme. Analyzing plasma samples from people with TTP in their families, the researchers found that, although plasma from children with the disease had no VWF-cleaving activity, plasma from their parents and some of their siblings (none of whom had TTP) showed about half the normal activity. This suggested that TTP is caused by a single recessive mutation in the gene responsible for the VWF-cleaving activity—that is, a mutation in one of an individual's two copies of the gene cuts down the enzyme activity, but for an individual to contract TTP, both gene copies must be mutated.

Gallia Levy, an M.D.-Ph.D. student in Ginsburg's lab, used this information in conjunction with genetic data from family members' DNA samples to determine the chromosomal location of the gene. Levy traveled to Cincinnati, to the lab of William Nichols, a former student of Ginsburg, who had the equipment and expertise for conducting the complex genetic analysis. "Gallia spent a week in his lab running all the genotypes. She came back with the data and sure enough, we had mapped the gene!" Ginsburg recounts. "We were pretty excited about it. She started analyzing more markers and narrowing the genetic location. When we got down to a manageable region of the genome, she went through the genes there, one by one, sequencing them in the blood samples from the TTP patients to see if we could find a mutation." Levy finally pinpointed the gene and found it to be mutated in all the children who had TTP. The gene, called ADAMTS13, encoded a protease—an enzyme that cleaves protein. At practically the same time, Sadler's team identified ADAMTS13 as the blood protease that cleaves VWF in particular.

Sadler and Ginsburg have learned much about ADAMTS13 since their discoveries 4 years ago. The general idea, says Sadler, is that ADAMTS13 regulates the activity of VWF in the blood. VWF recruits circulating platelets into a thrombus around a broken blood vessel. "If you don't have ADAMTS13, or if your own immune system destroys your ADAMTS13," Sadler explains, "these platelet thrombi grow out of control and you end up with TTP."

Sadler's group is currently trying to understand why some people produce autoantibodies to ADAMTS13 and to figure out what causes the vast differences in the severity of the disease in different patients. "We'll treat many of our patients with plasma exchange and they get better," he says. "Their antibody goes away, their ADAMTS13 comes back, and they're fine. But other patients may return to the hospital in a week or a few months with another episode. And each episode can be devastating. If we can identify patients with a high likelihood of relapse, and give them more intensive therapy up front, then I think we can save some lives." Ginsburg's lab is working toward a better understanding of childhood TTP. They recently developed a "knockout" mouse, lacking the ADAMTS13 gene, which mimics the human condition.

A commonsense treatment for TTP would be to administer recombinant ADAMTS13, Sadler explains. "That would be perfect for kids with congenital ADAMTS13 deficiency." It might also help adults with the acquired form of the disease.

Tragically, both researchers concede, the ultimate obstacle to a better treatment for TTP may not be scientific, but economic. "It's one of these rare examples where we have an opportunity to take a basic research finding straight to the bedside," Ginsburg says. "And it just isn't going to happen because of the financial realities of the pharmaceutical industry."

"We're talking about a disease that, at most, strikes maybe 1 in 100,000 people," Ginsburg says. "And pharmaceutical companies are not interested in developing a drug unless the market is a bare minimum of half a billion dollars a year. Otherwise, it's not worth their effort."

Meanwhile, the multiple strokes Jennifer Chamberlin suffered as a result of TTP took her sight and hearing, but her illness has been in complete remission for more than 4 years. Her doctors, including Sadler, credit rituximab, an immunosuppressive drug that kills antibody-making white blood cells and has shown remarkable effectiveness in treating autoimmune diseases. "We may be able to apply what we have learned about ADAMTS13 to identify high-risk patients like Mrs. Chamberlin, who could benefit from immunosuppression with rituximab at the time of first diagnosis," Sadler says. Ginsburg concurs: "That would be a real improvement."

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