How Studying Rare Disease Leads to Mechanistic Insights and Therapeutic Development: Lessons from Nonmammalian Models

Though individually rare, rare diseases collectively affect nearly 1 out of 30 individuals, highlighting the continued need for and importance of research on these disorders. We argue that the recent work in identifying and diagnosing previously undiagnosed diseases is only the beginning. To meet this need, animal models have played an important role in studying rare and undiagnosed diseases by providing functional and biological information to validate candidate disease genes. Specifically, nonmammalian models like nematode worms (Caenorhabditis elegans), fruit flies (Drosophila melanogaster), and zebrafish (Danio rerio) provide significant advantages to the scientific community and have, unsurprisingly, been essential in many advances in the rare disease field and beyond. Given this success, new priorities are emerging on how to use these animal models to drive therapeutic-focused research. In this review, we discuss how these common nonmammalian models have pointed to new therapeutic directions and are used to both test and create therapies. Through the characterization of genetic mechanisms and emerging protocols like drug repurposing, animal models have never been as important to the rare disease field as they are now. Ongoing mechanistic discoveries and therapeutic advances not only have the potential to improve our management of rare disease but may also have implications for more common disorders across multiple areas of medicine.