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Reversing cleft palate in-utero

Researchers have identified a new treatment to reverse the cleft palate defect in mouse pups — in-utero....

Researchers at the University of Utah (U of U) Health identified a molecular pathway responsible for the formation of cleft palate in mouse pups while identifing a new treatment to reverse this defect in-utero. These findings, published on September 5 in the journal Development, offer a new way to think about cleft development and could potentially generate treatments to prevent this common birth defect in people.

"As a clinician, I understand the devastating consequences of cleft palate," says Rena D'Souza, DDS PhD, a professor of Dentistry at U of U Health.

Cleft palate is one of the most common birth defects, affecting 6 in 2,651 children born in the United States. The lips form between 4 and 6 weeks of pregnancy (approximately Carnegie stage 16) and the palate forms between 6 and 12 weeks of pregnancy at Carnegie stage 17. In babies born with a cleft, the cleft forms when the bony tissue covering the roof of the mouth fails to join. Children with a cleft palate require reconstructive surgery and sometimes complex life-long treatments.

D'Souza and her team originally set out to investigate a different tissue: teeth. Using mice as a model, they initially planned to clarify the role of two sets of genes - PAX9 and Wnt genes - in regulating tooth formation. Unexpectedly, their work revealed how the interplay between these two genes at a critical window of development is needed for the palatal shelves to grow and fuse at the midline.
"It was really serendipitous. For the first time, we can show the involvement of the Wnt pathway during palate fusion."

Rena D'Souza, D.D.S., Ph.D., professor of Dentistry at University of Utah Health.

Like people born with a cleft palate, the two sides of the palate fail to fuse in mice lacking the gene PAX9. At the molecular level, D'Souza found another abnormality. The mice missing this gene had an increase in two genes, called Dkk1 and Dkk2, that block the Wnt signaling pathway.
D'Souza attempted to rectify that change by administering a pharmacological Wnt-based treatment that inhibited Dkk (WAY-262611) intravenously through the mother rat's tail vein during a critical window of the pups' gestation, when palate formation is initiated and ongoing.

Treatment restored palate fusion in all of the pups tested. The drug works by blocking the Dkk genes and restoring the Wnt pathway, with no adverse health effects after monitoring the mother mice and their pups exposed to the treatment for 18-months.

Along with cleft defects, PAX9-deficient pups also experience defects in their hind limb, as well as parathyroid and thymus glands. The Wnt-based treatment did not prevent the other defects, and the PAX9-deficient pups soon died after birth. D'Souza believes their premature death was more likely related to abnormal calcium levels, contrary to previous claims that early death was due to malformed palate.

D'Souza acknowledges that more work is necessary to ensure the Wnt-based therapy does not affect other organ systems negatively or produce long-term health problems.

"These seminal findings are exciting for the field, because Dr. D'Souza and her team have opened an interesting door into potential pharmacological therapies," says Ophir Klein, MD, PhD, Chief of Genetics at the University of California San Francisco. Klein, who is not an author on the study, believes the research presents a new strategy for treating human single-gene disorders, and may be useful in developing new approaches to reverse more defects in humans.

D'Souza believes these findings offer some babies born with cleft palate something that was missing before, hope.

"Clearly, there is more work to be done prior to implementation for humans, but it seems feasible to translate this research into Wnt-based treatments for people," she adds. Future work is needed to determine when it is safe and effective to deliver a drug to human babies in-utero or is it better to directly administer such a drug to newborns with palate defects.

Clefts of the palate and/or lip are the most common among human craniofacial malformations and involve multiple genetic and environmental factors. Defects can only be corrected surgically and require complex life-long treatments. Our studies utilized the well-characterized Pax9–/– mouse model with a consistent cleft palate phenotype to test small-molecule Wnt agonist therapies. We first show that the absence of Pax9 alters the expression of Wnt pathway genes including Dkk1 and Dkk2, proven antagonists of Wnt signaling. The functional interactions between Pax9 and Dkk1 is shown by the genetic rescue of secondary palate clefts in Pax9–/–Dkk1f/+;Wnt1Cre embryos. The controlled intravenous delivery of small-molecule Wnt agonists (Dkk inhibitors) into pregnant Pax9+/– mice restored Wnt signaling and led to the growth and fusion of palatal shelves as marked by an increase in cell proliferation and osteogenesis in-utero while other organ defects were not corrected. This work underscores the importance of Pax9-dependent Wnt signaling in palatogenesis and suggests that such a functional upstream molecular relationship can be exploited for the development of therapies for human cleft palates that arise from single gene disorders.

All authors: Shihai Jia, Jing Zhou, Christopher Fanelli, Yinshen Wee, John Bonds, Pascal Schneider, Gabriele Mues, Rena N. D'Souza

D'Souza conducted this work along with Shihai Jia, Jing Zhou, Christopher Fanelli, and Yinshen Wee at the University of Utah, School of Medicine, as well as John Bonds and Gabriele Mues at Texas A&M University and Pascal Schneider at the University of Lausanne, Switzerland.

The research received funding from the National Institutes of Health National Institute of Dental and Craniofacial Research and the Swiss National Science Foundation.

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Sep 18, 2017   Fetal Timeline   Maternal Timeline   News   News Archive

TOP: Normal palate followed by Cleft palate in two Pax9-/- mouse embryos.
Image Credits: Rena D'Souza

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