Modeling craniofacial and skeletal congenital birth defects to advance therapies

Abstract

Craniofacial development is an intricate process of patterning, morphogenesis, and growth that involves many tissues within the developing embryo. Genetic misregulation of these processes leads to craniofacial malformations, which comprise over one-third of all congenital birth defects. Significant advances have been made in the clinical management of craniofacial disorders, but currently very few treatments specifically target the underlying molecular causes. Here, we review recent studies in which modeling of craniofacial disorders in primary patient cells, patient-derived induced pluripotent stem cells (iPSCs), and mice have enhanced our understanding of the etiology and pathophysiology of these disorders while also advancing therapeutic avenues for their prevention.

Figure 1.

Pipeline for transforming insights from disease models into potential therapeutics for craniofacial disorders. Human genetic studies identify critical genes linked to craniofacial disease. Mechanistic studies, using primary patient cells, patient-specific iPS cells, and/or animal models, probe the disease gene’s role in craniofacial biology. Once the biological function of the gene is discovered, therapeutic targets can be identified. Having an in-depth view of the target’s biology aids in selecting therapeutic modalities, such as biologics, small molecules, stems cells, and possibly gene editing.