In a new study, scientists described a molecular pathway responsible for the cleft palate formation and found a new therapy to reverse the defect in mice in-utero, published in the journal Development. Professor Rena D'Souza said, "As a clinician, I understand the devastating consequences of cleft palate."
In U.S., 6 in 2,651 children born with cleft palate, an inborn defect. The bony tissue covering the roof of the mouth when fails to join during pregnancy leads to the formation of the cleft. Reconstructive surgery and complex life-long treatments required for children with a cleft palate.
D'Souza and associates clarified the role of PAX 9 and Wnt genes in regulating tooth formation using mouse model. The researchers found that the interaction between the PAX 9 and Wnt genes was essential for the palatal shelves to grow and fuse in the midline.
"It was really serendipitous," she said. The scientists for the first time revealed that the Wnt pathway involved in the palate fusion, she added.
The study reported that the PAX9-deficient mice developed a cleft palate. The scientists also found that Dkk1 and Dkk2 genes, which inhibit the Wnt signaling pathway, were increased in PAX9-deficient mice.
Hence, the researchers administered a Wnt-based treatment that inhibited Dkk (WAY-262611) intravenously through the mother mouse’s tail vein during the palate formation was initiated and on-going. The findings reported that the drug blocked the Dkk genes, restored the Wnt pathway and thus restored palate fusion in all of the pups tested. The mother mice and their pups were treated for 18-months and didn’t report any adverse effects.
PAX9-deficient mice also experienced defects in their hind limb, parathyroid, and thymus glands. However, the Wnt-based treatment did not prevent these defects that caused early death of PAX9-deficient pups. The previous study found that premature death was due to the malformed palate. But according to D'Souza, the premature death associated with abnormal calcium levels.
Further investigation required to ensure that the Wnt-based treatment does not affect other organ systems negatively or produce long-term health problems, said D'Souza.
Ophir Klein, said, "These seminal findings are exciting for the field”. A new way for the treatment of single-gene disorders in humans could be exploited for new approaches to reverse these defects in humans, he adds.
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.