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Scientists use drug to lengthen limb bones of mice with rare bone disorder, potentially avoiding surgery

Robinow syndrome disorders are very rare, but their consequences can be profound. Babies born with the genetic condition often have a cleft palate and develop short limbs by the time they reach 18 months old, along with facing the lifelong possibility of kidney and heart defects. Apart from surgical interventions, there is no treatment.

But scientists from Nationwide Children’s Hospital in Columbus, Ohio may have found a way to intervene on some aspects of the condition before it has a chance to develop. In a study published Feb. 15 in the journal Development, the researchers described how they were able to normalize the limb length of mouse pups with Robinow syndrome by dosing pregnant mice with a drug that corrects altered signaling pathways in cells. They believe their findings could apply to humans, too.

“The idea of treating the limb bones medically rather than surgically is a really important proof of principle, which we demonstrate in this study,” Rolf Stottmann, Ph.D., said in a press release. “We are very excited to test if this could work in the context of other genes associated with autosomal dominant Robinow Syndrome.”

The gene in focus is FRIZZLED2, or FZD2, which is vital to development before birth. It encodes a protein that controls the interactions between cells as organs and tissues are growing, and is a key part of the Wnt signaling pathways. These send signals into a cell through receptors at the cell’s surface. If the FZD2 protein is altered, some of those signals are lost and growth is disrupted.

Stottmann’s team was the first to link FZD2 to Robinow syndrome when it found that a mother and daughter with the condition both carried a mutated form of the gene that didn’t appear in unaffected family members. This suggested that FZD2 was behind the autosomal dominant type of Robinow syndrome, where only one copy of a mutated gene is required to cause a trait or disease to arise. In the new study, they used CRISPR/Cas9 genome-editing technology to replicate the mutation in a mouse model, inducing the same facial and limb characteristics in mouse pups born to mothers with the mutation as the ones seen in human children with Robinow syndrome.

The scientists knew from previous research by another team that a drug that stimulates some Wnt signaling pathways, the molecule IIIC3a, was able to prevent mouse pups with a different genetic mutation from developing cleft palates. To see if it would work in this case, too, they injected IIIC3a daily into a group of pregnant mice with Robinow syndrome beginning about halfway through their gestation period. The mouse pups born from the treated mice still had cleft palates, but the length of their limbs was almost normalized.

Why was the drug able to improve limb length, but not the cleft palate? According to the scientists, IIIC3a was acting on established, predictable signaling pathways, or canonical signaling pathways, that when corrected normalized the pups’ long bones. It could be that non-canonical signaling pathways—unique or alternative pathways that are less well characterized—are behind the cleft palate and that the drug in the context of the FZD2 mutation didn’t influence them.

Still, the researchers noted, bone length is much harder to correct than a cleft palate. From that standpoint, “[m]edical intervention would appear to be a very attractive option for therapeutic treatment, especially in the case where the genetic diagnosis could potentially be made years before long bone growth is concluded in human development,” they wrote in the paper.

The scientists’ future work will focus on better understanding how the FZD2 mutations affect Wnt signaling. They also hope to try their approach on other gene mutations associated with autosomal dominant Robinow syndrome.