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Prevention Is Better Than Cure: New Therapeutic Intervention Can Potentially Prevent Zaki Syndrome in Children

Researchers have discovered that administering the drug CHIR99021 during pregnancy may correct an orphan paediatric condition in developing fetuses.

A team of researchers from the Agency for Science, Technology and Research’s (A*STAR) Genome Institute of Singapore (GIS), and Rady Children’s Institute for Genomic Medicine has identified a previously unknown genetic condition affecting children and proposed a promising strategy to prevent its development – by administering a special drug called CHIR99021 during pregnancy.

Affecting approximately 3 per cent of all live births, structural birth defects are physical abnormalities that occur when a baby’s body does not develop normally in the womb. Most structural defects occur during the early weeks of pregnancy and can impact the skeleton and various organs, thus resulting in heart defects, cleft lip, missing, or protruding limbs, among many others. While the cause of most birth defects is largely unknown, scientists have found that there are several factors that may increase the risk of developing these abnormalities such as infections and exposure to certain medications or chemicals during pregnancy, as well as genetic disorders.

In recent years, scientists worldwide have identified children from Egypt, India, United Arab Emirates, Brazil, and the USA suffering from similar conditions. The genetic condition – now dubbed as Zaki Syndrome – affects the development of several organs of the body including the eyes, brain, digit, kidney, hair, and heart. Although different doctors were responsible for caring for the affected children, they all reported similar symptoms and had DNA mutations in the same gene. Upon further investigation using whole genome sequencing, doctors detected mutations in a gene called “WNT-less”, abbreviated WLS, which controls the signalling level of a hormone-like protein called WNT.

“We were perplexed by this paediatric condition for many years,” said Dr. Joseph Gleeson, senior author and paediatric neurogeneticist at Rady Children’s Institute for Genomic Medicine and the University of California, San Diego. “We observed children from across the globe with DNA mutations in the WNT-less gene, but did not recognise that they all had the same disease until doctors compared clinical notes. We then realised we were dealing with a new syndrome that can be identified by clinicians, and potentially prevented.”

One potential treatment is the use of a drug that counteracts the loss of the WLS gene. According to previous studies using a pre-clinical trial model and stem cell model of the Zaki syndrome, administering the drug could restore normal development. These hopeful findings encouraged researchers to further study how the drug could be administered to pregnant mothers and hopefully help to correct the condition in developing fetuses. However, Prof. Bruno Reversade, co-senior author, head of the Laboratory of Human Genetics and Therapeutics at GIS, and Research Director at the Institute of Molecular and Cell Biology (IMCB) commented, “While we have shown that it is possible to mimic WNT-deficiency with dedicated drugs, the real challenge was to overcome, and possibly rescue, this congenital disease.”

To determine whether the condition could be amendable through therapeutic intervention, the researchers generated stem cells and mouse models for Zaki Syndrome and treated it with a man-made drug that boosts WNT signalling, which is defective when WNT-less is mutated. The findings from their experiments were astonishing as it was revealed that the drug, called CHIR99021, could not only boost WNT signals but also restore development. The embryos successfully regrew their missing body parts and their organs began to develop almost normally, demonstrating the therapeutic effects of CHIR99021 and the potential for prevention if the condition is tackled during its early stages.

“The results were very surprising to us because it was previously assumed that structural birth defects like Zaki Syndrome could not be prevented with a drug,” said first author Dr. Guoliang Chai, a member of the team at Rady Children’s Institute for Genomic Medicine, who is currently at Capital Medical University in Beijing. “We could eventually see this drug, or drugs like it, being used to prevent birth defects if the fetuses are diagnosed early enough.” [APBN]

Source: Chai et al. (2021). A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion. New England Journal of Medicine, 385, 1292-1301.