Lab Mouse
18 September 2017

Tooth Study Stumbles On Cleft Palate Cure In Mice

A group of researchers at the University of Utah has stumbled across a promising treatment for cleft palate, a birth defect identified in about 2,650 children born in the United States every year.

Dental Researchers Create Genetic Cleft Palate Treatment

Led by Rena D’Souza, PhD, a professor in dentistry, the Utah-based team set out to better understand two sets of genes, known respectively as PAX 9 and Wnt. These genes, researchers have known for a while, appear to be crucial in the development of teeth. Their mode of action, however, is still poorly-understood, so the team set out to find more information by looking where medical researchers often look, in mice.

Mouse For Experimental Research

PAX9 & Wnt

The research began, but scientists soon discovered an interesting interaction. Beyond tooth development, PAX9 and Wnt seem to be involved in the closure of the palate, the span of hard and soft tissue that forms the roof of the mouth in both humans and mice. In mice (and humans) who lack PAX9 genes, palates don’t close properly; the two shelves of tissue that normally converge in the middle of the mouth fail to do so.

Looking even deeper, D’Souza and her colleagues found that mice who don’t have PAX9 genes also experienced abnormal increases in two other genes, Dkk1 and Dkk2. On the molecular level, these two genes work to block Wnt. Mice fetuses without the PAX9 genes, in whom Dkk1 and Dkk2 were knocking out the action of Wnt, were born with cleft palates. Could these genetic abnormalities be causing the birth defects?

Genetic Cure Spurs Palate Formation

D’Souza and her team tried to cook up a cure, injecting mouse mothers with a serum of chemicals that inhibit the Dkk genes, which themselves were stopping Wnt from working correctly. Crucially, the medicine was administered at a “critical window” in the development of the mother’s pups, right when the palate is being formed. It worked. All of the mouse pups treated in this way were born with complete palates, because Wnt had been allowed to do its job.

Is A Version For Humans On The Way?

The results were published in Development on September 5, 2017. “It was really serendipitous,” D’Souza told Futurism in a recent interview. “For the first time, we can show the involvement of the Wnt pathway during palate fusion.” That’s great, but what happened to the mice? The team followed mothers and pups exposed to the treatment for 18 months and didn’t notice any adverse health effects.

The pups without PAX9 genes died, but these mice are also born with a host of associated birth defects, including structural problems in the limbs and thymus gland issues. D’Souza believes that their premature deaths have something to do with abnormal calcium levels, although other researchers have suggested that mice with cleft palates die from malnourishment due to their condition.

As always, more research is needed – and planned – to make sure that the team’s treatment is safe and effective in more animal subjects. But many experts are already getting excited about the work in Utah and its implications for human children. Ophir Klein, MD, PhD, the Chief of Genetics at the University of California San Francisco called the findings “exciting” in an interview with a University of Utah publication. “Dr. D’Souza and her team have opened an interesting door into potential pharmacological therapies” for birth defects, Klein said.

Are Genes The Whole Story?

No, cleft palate is not solely genetic in origin. Like all other birth defects, it’s likely that orofacial abnormalities are caused in most cases by a complex interaction between genetic and environmental factors. Birth defect researchers consider viruses, pollutants and pharmaceutical drugs “environmental,” referring not to the air around us but to the womb environment in which babies develop. Many substances, including harmful ones, can travel from a mother’s blood to the circulatory system of her unborn child.

Some of these “teratogenic” chemicals can even increase the risk for birth defects. Valproic acid, a drug used to treat epilepsy and bipolar disorder, is one example of a drug that can increase the risk for cleft palate in significant ways. Another drug, Zofran, which is often prescribed to pregnant women as a morning sickness treatment, has also been linked to cleft palate, even inspiring a wave of product liability lawsuits against its manufacturer, GlaxoSmithKline.