The cure for cystic fibrosis might start in the womb

As an undergraduate student in the early 1980s, Marie Egan, MD, volunteered at the Children’s Hospital of Philadelphia. She’d often spend time in the hospital playrooms with children with serious illnesses. Many of them had cystic fibrosis (CF), a lethal genetic disorder.

“I saw these children who were very ill,” said Egan, vice chair of research in the Department of Pediatrics and interim chief of pediatric pulmonary, allergy, immunology, and sleep medicine at the Yale School of Medicine (YSM). “At the time, these kids often didn’t make it out of childhood.”

Today, people with CF are living longer but not without complications, especially in the lungs, pancreas, and other organs. There’s still no cure, and treatment usually comprises only symptom management.

But in a new study, Egan and several Yale colleagues describe the benefits of a novel approach for treating CF, and perhaps someday even curing the disease. Using in utero gene editing, the researchers developed a method to deliver corrective genetic material to the fetus of mice with CF via tiny particles called nanoparticles.

The results suggest that CF and other genetic diseases might eventually be curable in utero.

“If we could intervene while the organs are developing, then people would truly be cured of the disease,” said Egan, corresponding author of the study published in the journal Proceedings of the National Academy of Sciences.

The study was made possible by a multidisciplinary team across the YSM community. That includes members of the labs of Egan, who is also director of Yale’s Cystic Fibrosis Center and professor in the department of pediatrics and cellular and molecular physiology; Mark Saltzman, the Goizueta Foundation Professor of Biomedical Engineering and professor of cellular & molecular physiology and dermatology at YSM and of chemical engineering at Yale School of Engineering and Applied Science; Peter Glazer, the Robert E. Hunter Professor of Therapeutic Radiology and at YSM the chair of the department of therapeutic radiology; and David Stitelman, associate professor of pediatric surgery and obstetrics, gynecology & reproductive sciences at YSM. The research team also included first author Adele Ricciardi, of the University of Pennsylvania, a former member of Glazer’s lab.

“The manuscript represents the work of Yale undergraduates, medical students, graduate students, and residents, all of whom are devoted to careers in academic medicine, and we are very proud to be a part of their training,” said Stitelman, who is also surgical director of the Yale Fetal Care Center.

"If we could intervene while the organs are developing, then people would truly be cured of the disease."

-Marie Egan, MD

Cystic fibrosis arises from mutations in the CF transmembrane conductance regulator, or CFTR. Because the disease is caused by a single mutation, researchers saw it as a great candidate for gene editing, specifically in utero gene editing. The disease can cause serious damage to organs like the lungs and pancreas even before birth. Treating CF in the womb could mitigate this damage and improve the quality of life for those living with the disease.

“If you look at data today, our CF patients are now living into adulthood or even old age,” Egan said. “But the amount of therapy that people take, and the cost, is enormous. If you could actually develop a therapy where you could deliver it once and you wouldn’t have to worry about all this, wouldn’t that be great?”

"Our nanoparticles are made of materials that have long proven to be safe in humans. Control of their properties is critically important for the successful delivery of the gene editing agents into cells."

-Mark Saltzman

In the study, researchers used synthetic molecules similar to DNA — called peptide nucleic acids, or PNAs — to correct CFTR. PNA can be tweaked to bind to a particular gene containing a mutation in a strand of DNA, which can cause a lesion that the cell then removes itself. The gene is then corrected when a strand of DNA without the mutation takes its place.

“PNAs can induce gene editing and are well suited to in vivo applications because they are easily formulated into nanoparticles,” Glazer said.

The researchers delivered the PNA to the fetuses of mice using tiny synthetic particles called nanoparticles, which are the same size as viruses to correct the CFTR mutation before the mice were born.

“Our nanoparticles are made of materials that have long proven to be safe in humans,” Saltzman said. “Control of their properties is critically important for the successful delivery of the gene editing agents into cells.”

After receiving this treatment, and following their subsequent birth, the mice showed sustained improvement in their CF symptoms — even, in some cases, into adulthood. The PNA-loaded nanoparticles, researchers say, had corrected some of the dysfunction caused by the disease in the lungs but also other organs.

This research was done in partnership with the National Institutes of Health (NIH) through a grant that includes reimbursement for facilities and administrative expenses (also known as indirect cost reimbursements) that are necessary to ensure the safe conduct of research and compliance with federal regulations.

In February, the NIH announced it would dramatically cut such reimbursements to universities, including Yale. The courts have blocked the cuts, but the threat remains.

At stake is research that saves lives, strengthens the economy, and bolsters national interests. Yale projects in danger include research that saves infants born with heart defects, extends the lives of cancer patients, addresses mental health challenges, and prevents and slows the effects of Alzheimer’s disease.

Ultimately, researchers say, the study suggests the potential to cure cystic fibrosis using a single in utero gene editing treatment. While these findings are significant, Egan said, more research is needed to understand how the method might translate to a human population. However, she said, if the method proves effective in humans, it could lead to a groundbreaking shift in the treatment of genetic diseases, from solely managing symptoms to fixing the underlying causes.

“There’s so much for us to learn before that happens,” Egan said. “But I do think this is an incredible time, and we are seeing gene editing therapies in the clinic now. There are definitely some diseases where this approach has made a huge difference in the outcomes of children.”

The study was supported by grants from the National Institutes of Health, the National Institute of General Medical Sciences, and the Cystic Fibrosis Foundation.