Investigators at Yale School of Medicine (YSM) are developing a novel fetal therapy approach aimed at preventing cystic fibrosis (CF) before birth. Led by pediatric surgeon-scientist David Stitelman, MD, and a multidisciplinary team spanning gene editing, nanotechnology, and clinical CF care, the project explores the use of nanoparticle-mediated fetal gene therapy to change the course of this chronic disease.
The work brings together YSM leaders across disciplines, including Marie Egan, MD, in pediatric pulmonology, W. Mark Saltzman, PhD, who specializes in nanoparticle engineering, and Peter Glazer, MD, PhD, who focuses on high-fidelity gene editing.
CF affects about 2,500 newborns in the United States each year and is caused by mutations in the CFTR gene, which lead to thick mucus in the lungs and digestive tract. While recently approved CFTR modulator therapies have improved outcomes for many patients, these treatments require lifelong use and are not effective for all mutations.
The Yale team is pursuing a different strategy: delivering gene-based therapies to the fetus to prevent organ damage that begins in utero.
The approach uses biodegradable nanoparticles to carry treatments, such as messenger RNA and gene-editing tools, directly to developing fetal tissues. Early intervention offers several advantages, including access to rapidly dividing stem cells, increased DNA repair activity, and the chance to prevent disease before it appears.
“Our goal is to intervene before the disease phenotype is established. By targeting the developing fetus, we have a unique opportunity to prevent the organ damage that defines cystic fibrosis at birth,” Stitelman says.
The project, supported by a Cystic Fibrosis Research Institute New Horizons Research Program grant, focuses on two complementary strategies. In one, nanoparticles deliver CFTR mRNA to temporarily restore protein function in affected tissues. In the other, researchers use a high-fidelity gene-editing system based on peptide nucleic acids and donor DNA to correct disease-causing mutations at the genomic level.
Unlike conventional gene-editing approaches, this system does not rely on nucleases, reducing the risk of off-target effects and improving safety for potential clinical use.
Preclinical studies in mouse models have shown that a single fetal treatment can lead to measurable correction of CFTR function, better ion transport in airway and intestinal tissues, and less inflammation. Investigators have also shown efficient nanoparticle delivery to the fetal pancreas, bowel, and lung—key targets for CF therapy—with no evidence of harm to fetal development or germline cells.
The team is now working to optimize nanoparticle design, improve delivery efficiency, and further evaluate safety, with the goal of advancing toward early-phase clinical trials.
If successful, the approach could offer a one-time, in utero treatment for CF and serve as a platform for addressing other monogenic diseases before birth.