published in the journal Clinical Immunology in 2010. New T cells developed three to five months following the procedure. Patients were able to stop receiving antibiotics and immunoglobulin replacement therapy, a treatment that infuses antibodies that immunodeficient patient lack. More than 70 percent of the patients who received Markert’s treatment survived.
The most common side effect, observed in 13 patients, was thyroid disease, which causes the thyroid gland to produce too much or too little thyroid hormone. The disease may be unrelated to the transplant and could be part of DiGeorge, the paper says. The most serious side effect was intestinal inflammation, found in one patient. The diarrhea was treatable but the patient died from fungal pneumonia, according to the paper. Markert says the patients who died had infections before the transplants.
The therapy has also been tested in Europe, albeit in smaller numbers. Of 12 patients who received transplants, autoimmune complications developed in seven, according to results published in December in the Journal of Allergy and Clinical Immunology. Two died from pre-existing infections. T cell counts did not reach normal levels in the surviving patients, but they were able to clear pre-existing infections as well as infections acquired later.
For much of the past 25 years, Markert has scrambled for funding to support her research. Though Duke has a strong record of turning its medical research into new startups, Markert says she found little traction in the investment and biotech communities. Two years ago, Markert’s grant support was drying up. A phone call changed her fortune.
Years before Pavan Cheruvu became an executive at drug developer Roivant Sciences, he was a Duke undergraduate student. During a return visit in 2016, one of his former professors told him about the university’s DiGeorge research, Markert says. Intrigued, Cheruvu contacted her.
Roivant’s business model involves finding experimental treatments that have been either overlooked or set aside by pharmaceutical companies. The company, which maintains sites in Switzerland, New York, San Francisco, Cambridge, and Durham, NC, acquires the rights to such compounds and supports them with the resources to complete clinical trials. If all goes well (and not all has gone well for Roivant’s bets) the company applies for FDA approval. In 2016, Roivant formed Enzyvant as a rare disease-focused subsidiary. Last year, Enzyvant licensed Duke’s thymus tissue technology. The company now funds Markert’s research.
Under Enzyvant, Markert’s therapy has the temporary name RVT-802. It has since become one of the first experimental treatments to receive the FDA’s Regenerative Medicine Advanced Therapy (RMAT) designation. Created by the 21st Century Cures Act, this regulatory pathway streamlines the review process for new cell therapies and tissue engineering products that treat life-threatening conditions. Enzyvant CEO Alvin Shih expects the company will be ready to file for FDA approval later this year. If the treatment reaches the market, Shih says Enzyvant will produce it at Duke, at least at first. That’s because the expertise with the technology is at the university, he says.
Enzyvant estimates that complete DiGeorge anomaly affects one in every 300,000 infants. The company expects to find them through tests now routinely done on small blood samples taken from newborns to find a variety of diseases. Though this newborn screening does not currently test for the genetic defect that causes DiGeorge, Shih notes that T cell levels are part of the screening in 48 states. That test, meant to detect a different immune system disorder called severe combined immunodeficiency (SCID), will also detect DiGeorge, he says.
Others are developing experimental immune system treatments. Scientists at UCLA have created an artificial thymus meant to produce T cells that treat cancer. The Fred Hutchinson Cancer Research Center in Seattle has tested donor stem cell transplants to treat immunodeficient patients, including those with DiGeorge. Markert says gene therapy, the replacement of defective genes with functioning ones, may one day offer yet another option. In the early 1990s, Markert had grant support for gene therapy research in SCID. She didn’t realize then that DiGeorge would become her life’s work.
“It was answering the telephone and trying to help one child,” Markert says. “And that led to helping all these children.”
Photo by Flickr user City of Boston Archives via a Creative Commons license.
