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University of Iowa researchers have successfully tested a technique that stimulates a gene to prevent craniosynostosis, a condition that causes infants' skulls to close prematurely.

Craniosynostosis occurs when one or more joints between the bones of a baby's skull close prematurely, leaving a lack of space for the growing brain to expand. This can cause deformities in head shape and facial appearance if not treated surgically. Some studies have stated the condition can occur in as many as 1 out of 2,200 live births.

The Iowa researchers identified a single gene, miR-200a, and created a nano-sized packet that was injected just below the scalps of newborn mice. The nano-packets migrated to the joint region in the mouse skull and released the miR-200a gene, causing cells to stimulate more production of the gene. That production, known as gene expression, instructed the joints, or sutures in the skull, to not fuse, thus allowing room for the infant mice's brains to expand.

"This is the first demonstration of a gene therapy approach for craniosynostosis that we know of," says Brad Amendt, professor of anatomy and cell biology in the Carver College of Medicine, professor of orthodontics in the College of Dentistry, and the study's corresponding author. "This will save a lot of trauma for children."

The study, "Inhibition of craniosynostosis and premature suture fusion in Twist1 mutant mice with RNA nanoparticle gene therapy," was online Aug. 22 in the journal Science Advances.

There are more than 40 genes considered to be involved in craniosynostosis. Amendt zeroed in on the miR-200a gene after finding that it appeared to have a role in craniofacial development. His team tested the hypothesis by first blocking the gene in infant mice. The mice in those experiments developed craniosynostosis.

Next, Amendt's group partnered with Kevin Rice, professor in the College of Pharmacy and a co-author on the study, to come up with a formulation, or recipe, to deliver the miR-200a gene and coax cells to produce it. That formulation involved a 95-nanometer-sized package that housed the gene, small enough for the cell to recognize it and welcome it in, like an invited houseguest.

"The cells have a process where they'll see this nanoparticle, take it up, and uncoat the particle, so that we can release the gene. Then a cell can express it," Amendt explains.

The researchers injected the nano-packets a single time into eight infant mice that had been genetically programmed for craniosynostosis. None of the eight developed the condition. Moreover, the skull sutures remained open for 17 days, allowing room for the mice's brains to grow as normal and long enough to demonstrate the lasting effect of gene treatment, the researchers report.

"We've shown there's no toxicity with our system and there are no adverse effects either on the skull or with any cancer," says Amendt, who is director of the Craniofacial Anomalies Research Center at Iowa.

For now, it is nearly impossible to detect craniosynostosis before a child is born. But once detected, intervention would be minimal: Surgeons would need to perform a procedure known as endoscopic strip craniectomy, which then could be followed by the gene-led treatment.

Amendt has applied to the U.S. Food and Drug Administration to test his gene therapy on human infants. He hopes to begin clinical trials in the next one to two years.

"My research is really focused on better patient health and how we can help patients," he says. "So, it's very satisfying for us to be able to show how we have a potential treatment for children with craniosynostosis."

The first author is Samuel Swearson, a student in the Interdisciplinary Graduate Program in Biomedical Engineering at Iowa, who performed the mice experiments. Additional co-authors are Steve Eliason, research lab manager in the Amendt research group; and Dan Su, from Stanford University.