Translational Genomics Research Branch
Division of Extramural Research
This initiative is intended to accelerate research using animal models and precision medicine approaches to develop in utero treatments of congenital dental and craniofacial disorders. The long-term goal is to lay the groundwork for delivery of in utero treatments in human.
Congenital disorders are characterized by structural and functional anomalies in affected organisms and individuals, and if left untreated, are often irreversible. Some congenital disorders, including those in dental and craniofacial structures, have been associated with specific risk and causal factors that are genetic, epigenetic, nutritional, teratogenic and environmental. Delivering in utero therapies during an early enough time window and targeting the defects at the molecular, genetic, genomic, cellular, tissue, or functional levels can repair or arrest the development of congenital disorders and, in some cases, prevent prenatal lethality.
Gaps and Opportunities
There is a lack of safe and efficacious in utero therapies for most congenital dental and craniofacial disorders, many of which result in severe and irreversible malformations before birth. The field is now poised to fully unlock the potential of precision medicine for treatments of these disorders in animal models and ultimately translate them to humans. Advances in genetic, molecular, and imaging technologies have made it possible to predict, diagnose, and detect disorders early in gestation. Such capabilities will guide the development and clinical translation of the treatments to humans. Moreover, research has been pursued actively with promising progress towards restoring normal functions of the genome and epigenome or normal functions and morphologies of targeted cells and tissues. Examples of initial success are replacement of dysfunctional gene expression products using peptides (molecular approach); modulation of perturbed signaling pathways using small molecules (molecular approach); CRISPR/Cas-based reprograming of somatic epigenomes to modulate cell fate (genomic approach); various genetic modulations that restore normal functions of the genome such as replacing a mutated gene with its wildtype, inactivating a mutated gene, or introducing a modified gene into an organism through knock-in, knock-out, and other approaches (genetic approach); and in utero stem cell transplantation targeting damaged cells or tissues (bioengineering approach). In terms of the delivery of treatment modalities, advances are being made with ex vivo, in vivo, and in situ deliveries to animals or humans. More advanced endeavors have already led to clinical trials of in utero treatments of, e.g., X-linked hypohidrotic ectodermal dysplasia and lysosomal storage diseases.
This initiative will build on the knowledge, know-how, and resources resulting from various NIDCR- and NIH-funded research. Existing and new animal models will serve this initiative well. The initiative can also leverage the NIH Common Fund Somatic Cell Genome Editing program, which focuses on accelerating research to deliver gene editing cures for various disorders. Finally, NIDCR and other NIH intramural researchers conducting research in this area can readily join forces with funded extramural investigators to advance the field.
Congenital dental and craniofacial disorders of interest include but are not limited to tooth agenesis, orofacial clefting, craniosynostosis, and hemifacial microsomia. In utero treatments can use molecular, genetic, and genomic approaches to correct alterations to genomes, epigenomes, or specific biological pathways in affected somatic cells in a timely fashion to ensure or resume normal development. Bioengineering approaches, which are applicable to treating some functional and structural anomalies that are associated with genetic, genomic, teratogenic, and environmental factors, can be explored as well. Treatment development for genetic disorders can target monogenic, oligogenic, and polygenic disorders, and tackle loss- and gain-of-function mutations, genetic heterogeneity, and somatic mosaicism. For delivery of treatment modalities, local (to affected cells or tissues) or systemic delivery, delivery of single or multiplexed reagents, and use of viral or non-viral (such as nanoparticles) vectors, are all among what can be investigated. Of importance for ultimate clinical translation of the treatments developed, off-target effects, cellular and tissue tropism, clinical suitability of therapy reagents, and other challenges that affect precision, efficacy, safety, dosage, and the ultimate clinical outcome, should be tackled in small and large mammalian models.
This program is intended to ultimately realize in utero treatments or cures for human congenital dental and craniofacial disorders. Treatments developed may be readily applicable to other defects sharing the same early developmental pathways.
In the past ten years, NIDCR has supported research to identify key signaling factors functioning in early tooth development and palatogenesis, including the Wnt, EDA/EDAR, Pax9, and Msx1 pathways. Within this portfolio, a few projects aimed to develop therapeutics for tooth agenesis and palate morphogenesis, and a recent breakthrough was the rescue of palate morphogenesis in embryonic mice. Other NIH institutes have supported the development of in utero therapies for other diseases using animal models or targeting human study participants, including in utero CRISPR-Cas9 based gene editing of metabolic genes. This initiative would expand our portfolio in novel in utero treatments for dental and craniofacial disorders leveraging advances in technologies.
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