A basic biological question leads to the first FDA-approved treatment for rare blood disorder
In November 2023, the U.S. Food and Drug Administration approved TAK-755 (commercial name Adzynma) as the first treatment for a rare but potentially lethal blood disorder.
This new treatment marks the second time in his career that David Ginsburg, M.D., has helped bring an FDA-approved drug to the clinic, without ever specifically setting out to treat a disease.
“Sure, if we can cure a disease, I'd love to. But that's not really what drives most of us as scientists,” says Ginsburg, a geneticist and professor at the University of Michigan Life Sciences Institute and Medical School. “What drives our day-to-day work in the lab most of the time is the basic biologic question — that sort of ‘gee whiz, how does that work?’”
In the early 2000s, the basic biological question that had piqued Ginsburg’s interest centered on a unique clotting pattern associated with congenital thrombotic thrombocytopenia purpura (TTP).
Finding the protein that isn't there
Patients with TTP develop small blood clots throughout their body, blocking blood flow to essential organs including the brain and kidneys. Compared with standard blood clots, the TTP clots were very rich in platelets and contained much more —unusually long forms — of a protein called von Willebrand’s factor (VWF).
“These patients were clearly missing something that would typically process VWF into smaller pieces. And it seemed likely that was causing the clots,” he explains. “That connection to VWF is really what got us interested in this.”
Ginsburg completed his medical training and postdoctoral research in hematology. As a postdoctoral researcher, he was the first to successfully clone the von Willebrand gene, mutations in which cause the most common inherited bleeding disorder (a discovery that led to the other FDA-approved drug from his research).
That initial discovery served as a launchpad for Ginsburg’s research program at U-M, which has expanded over the past three-plus decades to investigate other rare blood disorders, blood vessel architecture, and even the mechanisms that allow proteins to be shuttled within and outside of cells.
When Ginsburg raised the question of a TPP–VWF connection with his lab, a graduate student named Gallia Levy asked to take on the task of finding which gene could be at the root of the problem. A colleague from the Albert Einstein College of Medicine, Han-Mou Tsai, had measured patients’ ability to cleave VWF, and also had the family pedigrees for these patients, opening the door to tracing the genetic cause.
“The Human Genome project was not yet complete, so there was a real possibility that gene was in a region that hadn’t been sequenced yet. We didn’t have the option of sequencing an individual’s whole genome, the way we can today, so we really didn’t know what we would find.” recalls Levy, M.D., Ph.D., who is now the chief medical and product strategy officer at Spark Therapeutics. “It was exciting and at the same time felt like a lot of responsibility.”
Through a technique called positional cloning — which involves first figuring out on which chromosome the potential gene of interest lies, then narrowing down the gene candidates and testing them one by one — Levy found the culprit.
It was a gene that’s responsible for making a protein called ADAMTS13, which typically chops up the VWF into appropriate sizes. Without the properly functioning gene, patients with congenital TTP were missing ADAMTS13, resulting in VWF chains that were too long and too sticky to allow proper blood flow. These findings were featured on the cover of a 2001 issue of the journal Nature(link is external).
"The critical thinking I learned by doing basic research ... is something I still use every day." - Gallia Levy, M.D., Ph.D.
Long-term impacts in the clinic and beyond
With the gene and protein identified, it was now possible to generate a purified version of ADAMTS13, also known as the recombinant protein. The U-M Office of Tech Transfer (now Innovation Partnerships) worked to license the rights to the ADMATS13 sequence to Baxter International (now Takeda), and the discovery became the basis of the new FDA-approved treatment.
Since the early 1980s, patients with congenital TTP have been treated with plasma from healthy human blood donors. And while that treatment has lowered the disease’s fatality rate from approximately 90% down to 10 to 20%, it is not entirely without risks.
“The big advantage of the recombinant protein, over human plasma, is that you’re just getting this pure, clean protein,” Ginsburg explains. “With this new treatment, we know exactly what is going into the patient, and at exactly what dose, and we don’t risk exposing the patient to anything else that may be in human plasma.”
The ADAMST13 research continues to influence both Ginsburg research program and Levy’s career, even 20 years later. Researchers in the Ginsburg lab still use animal models of TTP to probe new questions in clotting and blood vessel function. And Levy says the discovery — and the foundational science skills she gained — set the trajectory for her career in industry.
“Even though I don’t do any basic research anymore, the critical thinking I learned by doing basic research under David’s mentorship is something I still use every day,” she says.