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CRISPR: Giving Cleft Lip & Palate a Facelift

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12 Dec 2023, 1:00 pm

<blockquote> <h3>Fast Facts:</h3> <ul> <li>Cleft lip and palate are the most common birth defects in the United States with approximately 4,400 children born with a cleft lip and 2,700 born with a cleft palate each year – that is about 1 in 700 babies born with either (or both) a cleft lip and cleft palate.</li> <li>Babies born with a cleft lip and/or palate have a higher risk of being malnourished because they have difficulties breast and bottle feeding since they are not able to form a seal with their mouths. They are also at a higher risk for respiratory infections.</li> <li>Cleft defects arise in the early stages of fetal development; therefore, babies born with the defect must endure many painful corrective surgeries to fix the clefts.</li> <li>Scientists have identified the four genes that are involved in cleft lip and palate – PAX9, Wnt, Dkk1 and Dkk2.</li> </ul> </blockquote> Forty years ago, having a "test-tube baby" was considered controversial. Now, however, having a "test-tube baby", or in vitro fertilization (IVF), is more common and considered a mainstream medical treatment for infertility. Now, the new reproductive controversy is the use of an out-of-science-fiction concept, known as CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat), to create "designer babies" free from genetic defects and disorders. CRISPR is a powerful tool for editing genomes. It allows scientists to easily alter DNA sequences and modify gene function. Using CRISPR, certain genes responsible for various defects and disorders can be edited out of a baby’s genome. Since scientists have now identified the four genes that are responsible for cleft lip and palate, CRISPR could end the need for children to undergo painful reconstructive surgeries to repair these congenital deformities by snipping the genes responsible. <h2>The ABCs of cleft lip & palate</h2> There are several different types of facial clefts. The most common are cleft lips and palates making these the most common birth defects in the United States. Approximately 4,400 children are born with a cleft lip and 2,700 are born with a cleft palate each year – that is about 1 in 700 babies born with either (or both) a cleft lip and cleft palate. A cleft palate occurs when the tissues that make up the roof of the mouth, or palate, does not close and fuse completely. In some instances, a cleft palate is accompanied by a cleft lip, which occurs when the upper lip does not form properly leaving a gap. <figure><img alt="" src="https://cdn.storymd.com/optimized/aARMp5Uvqz/original.jpg" /> <figcaption>Baby with cleft lip. Source: CDC</figcaption> </figure> Cleft lip and palate are not life-threatening birth defects, but children born with one or both defects face many issues. It is not simply a cosmetic problem, but rather, babies born with a cleft lip and/or palate have a higher risk of being malnourished because they have difficulties breast and bottle feeding since they are not able to form a seal with their mouths. They are also at a higher risk for respiratory infections. Speech difficulties can also arise since the palate is crucial in forming sounds, and some may struggle with stigmatization due to the clefts being such a visible facial difference. Because cleft defects arise in the early stages of pregnancy, there is no way to ensure that a baby’s facial features fuse and form correctly during development. As a result, babies are born with the congenital deformity. The only way to fix a cleft lip or palate is for them to endure many painful corrective surgeries, often beginning when they are a few months old. <h2>Clefts are in the genes</h2> For many decades, scientists didn’t know precisely what caused a baby to be born with a cleft lip and/or palate. They did know it was a genetic phenomenon – but not necessarily hereditary. Turns out, the consensus among scientists is that it is a combination of genetic and environmental factors that contribute to the cause of cleft lip and palate. In fact, scientists from the University of Washington have now identified the four genes that are involved in forming the palate and upper lip. The two sets of genes, PAX9 and Wnt, must work together to ensure the palate grows and fuses during a critical period in fetal development. During their research in mice, the scientists noticed that the two sides of the palate didn’t fuse properly in mice lacking the PAX9 genes. As well, those mice had an increase in two other genes, called Dkk1 and Dkk2, that blocked Wnt gene signaling. More simply put, cleft lip and palate occurs when the Dkk1 and Dkk2 genes interfere with the PAX9 and Wnt genes from functioning properly. This is a major breakthrough because, for the first time, scientists were able to identify the specific genes involved in cleft lip and palate. <h2>Gene therapy closes the "cleft" gap</h2> With this discovery, scientists from the study wanted to determine whether they could manipulate the genes involved to prevent the defect from occurring. To that end, they administered a drug to the mother mouse during that critical moment when palate formation happens – a gene therapy of sorts. The result: the drug was able to block the activity of the DKK genes and activate the Wnt signalling pathways. By using a drug to alter gene activity of mouse embryos, the palate of the mice pups was able to grow and fuse properly during development. This opens the door for the possibility of using CRISPR to edit those specific genes responsible for cleft lip and palate. <h2>CRISPR giving cleft lip and palate a facelift</h2> Now that scientists know that proper functioning of the PAX9 and Wnt genes are necessary for complete fusion of the palate and upper lip, and that the Dkk1 and Dkk2 genes can interfere with PAX9 and Wnt genes, the essence of CRISPR is simple. At the embryonic stage, scientists can do many things to edit the cleft lip and palate genes. First, they can find the sequence of DNA that make the Dkk1 and Dkk2 genes, snip that portion of DNA to completely remove those genes, thus, preventing the Dkk1 and Dkk2 genes from interfering with Wnt signalling. Alternatively, scientists can turn on the PAX9 and Wnt genes so that they are constantly active while turning off the Dkk1 and Dkk2 genes without altering the DNA sequence. With PAX9 and Wnt working continuously without Dkk1 and Dkk2 interfering, the fusion of the palate and upper lip can happen without interruption. While, theoretically, CRISPR could be the key in preventing babies from having to endure being born with cleft deformities, in utero gene therapy is still very controversial and may not yet be ready for real-world clinical applications. <h2>More on Cleft Lip and Palate</h2><ul><li><a href="https://soulivity.storymd.com/journal/pwgr5do14j-cleft-lip-and-palate" target="_blank">Cleft Lip and Palate: Causes, Diagnosis, Treatment</a></li><li><a href="https://soulivity.storymd.com/journal/wlaxraysem-genome-editing" target="_blank">Genome Editing and Human Disease</a></li><li><a href="https://soulivity.storymd.com/journal/j478zb8inj-genomics-101" target="_blank">Genomics 101</a></li></ul>

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