Duke scientists join team involved in the first use of fetal therapy for Pompe disease

Experts at Duke Health were among a multi-national team involved in treating a fetus for infantile-onset Pompe disease using an enzyme replacement therapy - a first in the world.

The case, reported online Nov. 9 in the New England Journal of Medicine, highlights the potential for introducing a therapy for Pompe disease prior to birth. Even in the womb, the lysosomal storage disease damages major organs. By initiating enzyme replacement before birth, the care teams anticipate better outcomes than are typical with post-birth treatment.

Duke's scientists involved in the case included world-renowned Pompe disease expert Priya Kishnani, M.D., medical director of the Y.T. and Alice Chen Pediatric Genetics and Genomics Research Center at Duke University School of Medicine, and Jennifer Cohen, M.D., a geneticist and assistant professor in the Department of Pediatrics at Duke University School of Medicine.

Kishnani and Cohen collaborated with physicians at the University of California at San Francisco, a leader in fetal procedures; CHEO, a pediatric hospital and research center in Ottawa, Canada; and The Ottawa Hospital in Canada, where the treatment occurred.

The fetus received six enzyme replacement treatments administered into the umbilical cord by maternal fetal medicine specialists at The Ottawa Hospital. After she was born, the baby, Ayla, began receiving standard therapy and is doing well at 16 months of age. She has normal cardiac and motor function and is meeting developmental milestones.

From our long-standing work at Duke treating patients with Pompe disease, we know first-hand the critical importance of earlier initiation of treatment. Our ability to offer a new treatment opportunity to this family and potentially change the course of this difficult disease has made this collaboration and project groundbreaking."

Jennifer Cohen, M.D., co-first author of the NEJM paper

Babies born with infantile-onset Pompe disease typically have enlarged hearts and die within two years if untreated. The disease is rare, seen in less than 1/100,000 live births, and is caused by mutations in a gene that makes acid alpha-glucosidase, an enzyme that breaks down glycogen. Without it or with limited amounts, glycogen accumulates dangerously in the body.

Duke has played a pivotal role in many advances in the field of Pompe disease, including developing alglucosidase alfa as the first Food and Drug Administration-approved enzyme replacement therapy for Pompe disease; identifying the role of high and sustained antibody titers to the therapy; using biomarkers to follow treatment response; and establishing immune tolerance induction protocols for the most severe patients.

"All of these advances provided crucial guidance and insight for the fetal therapy used during baby Ayla's care," said Kishnani, who is co-senior author on the NEJM publication. "The intrauterine therapy represents a new frontier for patients with Pompe disease."

The case provided a unique opportunity to move forward with the in-utero procedure. The child's parents had had two previous children born with Pompe disease, both of whom died. When pregnant with Ayla, the mother underwent tests that confirmed Pompe disease yet again.

Under usual circumstances, the patient's parents would have traveled from their home in Ottawa to the UCSF Benioff Children's Hospital Fetal Treatment Center, which has received FDA approval to treat Pompe and other lysosomal storage disorders using enzyme replacement therapy in-utero.

When COVID-19 restrictions made international travel unfeasible, however, experts from the two Canadian hospitals, UCSF and Duke met the family by video to discuss alternatives. UCSF shared the treatment protocol with the team in Ottawa. Throughout the process, the entire team met weekly by video to discuss the health of the mother and fetus and to monitor the response to treatment.

Pranesh Chakraborty, M.D., a pediatrician and metabolic geneticist at CHEO and co-lead of the case study, has provided care to the family for years.

"Having had the privilege and heartbreak of walking alongside families who have lost children to these devastating diseases, this work is very important to me," Chakraborty said. "Seeing how well Ayla is doing, it is important to pursue clinical trials to establish whether this kind of fetal therapy will be a good option for other families when treatment in the newborn period just isn't early enough."

The researchers hope the success of this first application and publication of the case study will increase awareness of the UCSF clinical trial among parents at known risk of passing on these diseases and the physicians who treat them.

"We really needed this multidisciplinary group of people to lend their deep expertise to all aspects of care," said co-senior author Tippi C. MacKenzie, M.D., who holds a Benioff UCSF Professorship in Children's Health and a John G. Bowes Distinguished Professorship in Stem Cell and Tissue Biology. "Enzyme replacement therapy is a new frontier in the field of fetal therapy."

In addition to Cohen and Kishnani, researchers at Duke who are co-authors and were involved in the case include Deeksha Bali, Ph.D., and Sarah Young, Ph.D., who led the biochemical analyses for the patient during and after birth and interpreted the data, and pathologist Kyle Strickland, M.D., who conducted placental pathology and identified control samples to validate the efficacy of the in-utero treatment response.

Additional members of the Duke Pompe research team who provided expertise include Ankit Desai, M.D., Eleanor Rodriguez-Rassi, Seung-Hye Jung, Ph.D., and Catherine Rehder, Ph.D.