Drug developed at Duke is approved by FDA as only therapy for congenital athymia

The phone rang into the pediatric unit that Louise Markert, M.D., Ph.D., was staffing as a junior faculty member in 1991. Had she not answered, there would have been little hope for the more than one hundred patients who were subsequently treated.

The call was from a doctor in Tennessee, seeking insights from Duke's renown pediatric immunology team to help him treat a child who was born without a functioning thymus gland. That question launched Markert on a 30-year exploration for a viable treatment.

"I had heard of DiGeorge syndrome," Markert said, referring to the condition that afflicted the child in Tennessee. "Children with DiGeorge syndrome often have 3 problems: no thymus, a heart defect and low calcium levels that can lead to seizures. I hadn't ever treated a patient with DiGeorge syndrome – I was working on mice and thinking about research in gene therapy."

Prompted by that call for help, Markert recalled hearing about earlier experiments using cultured thymus tissue to build the immune systems of some children born without the gland. Most of those children died, but she thought there might be a way for thymus tissue to work and generate an immune system if she could bring together the right expertise at Duke.  

Throughout much of the next three decades, she honed the approach, benefitting from research collaborations with renowned colleagues at Duke, including Barton Haynes, M.D., who had done early lab studies in animal models. On October 8, the FDA approved a regenerative medicine based on Markert's pioneering work as the only therapy for congenital athymia, a grouping of rare diseases such as complete DiGeorge Syndrome that are characterized by the lack of a functioning thymus. Without the gland, which trains the body's T-cells to fight pathogens, seemingly harmless infections can be fatal. Without treatment, infants with congenital athymia conditions typically die by the age of three.

The newly approved therapy, which Duke licensed to Enzyvant Therapeutics, GmbH for development in 2016, uses thymus tissue that undergoes a series of intricate processes and then is implanted in babies with athymia, where it selects T-cells to recognize and attack pathogens.

It really has been an incredible journey."

Louise Markert, M.D., Ph.D.

Before Markert answered that phone call in 1991, the medical literature chronicled a few cases in which doctors retrieved thymus tissue from pediatric heart patients and implanted it in babies who lacked the gland, but it was not successful.

In 1997, Markert, Haynes and colleagues at Duke published a case study chronicling a first success in an infant with DiGeorge syndrome. That person is still alive.

Word spread, adding to Duke's reputation as a leading center for treating children born with certain types of severe immunodeficiency. Markert began receiving patient referrals from doctors throughout the U.S. and beyond and soon thereafter initiated a first clinical study.

In all, there have now been 10 clinical studies to investigate this treatment, including 105 patients. In an analysis of those patients enrolled since the 1990s, the estimated survival rate is 77% at one year and 76% at two years. For patients who were alive at one year following treatment, the long-term survival rate was 94% at a median follow-up of 10.7 years.  

Three of Markert's early patients are now in their 20s.

For Zelene Turner, whose daughter, Jayla, was born with DiGeorge syndrome 14 years ago, Markert's therapy was lifesaving. Doctors near the family's home at the North Carolina coast were initially stumped about what was causing baby Jayla's rash, but one physician suspected the immune disease and referred the family to Duke.

"We were so scared," Turner said. "She was nine months old when she got the treatment, and she was so sick. I was afraid to hold her. And then after we left the hospital, we had to be isolated at home — we did not want her exposed to anything that people just normally pick up."

Turner said she worried for three years, keeping visitors at bay and her house spotless, but eventually began to ease up. Now Jayla is in the 9th grade, an honor roll student in public school and, while still more fragile than most children, enjoys a mostly normal life.

"To look at her you'd never know," Turner said. "She's doing great. And those years I spent with her, I saw so many of the milestones that children normally reach. She is winning academic awards, and is interested in gymnastics, cheering and volleyball, she loves arts and cooking. She is awesome!"

With her long quest now fulfilled, Markert is focusing on other conditions that might be helped by cultured thymus tissue technology. A treatment team led by Paul Martin, M.D., Ph.D., and his colleagues in the Division of Pediatric Transplant and Cellular Therapy have now been caring for these patients when they come to Duke for treatment. John Sleasman, M.D., the chief of the Pediatric Division of Allergy Immunology and Pulmonary and his team, provide assistance with the immunologic evaluation of the patients.

Markert's team includes Jie Li, Stephanie Gupton and Betty McCarthy. "It has been a real team effort, and an amazing experience," Markert said. "I've had great help from across the Department of Pediatrics from so many wonderful people who really wanted to help these babies."