Abstract
Achondroplasia (ACH) and hypochondroplasia (HCH), the two most common types of dwarfism, are each caused by FGFR3 gain-of-function mutations that result in increased FGFR3 signaling, which disrupts chondrogenesis and osteogenesis, resulting in disproportionately shortened long bones. In this study, TYRA-300, a potent and selective FGFR3 inhibitor, was evaluated in 3 genetic contexts: wild-type mice, the Fgfr3Y367C/+ mouse model of ACH, and the Fgfr3N534K/+ mouse model of HCH. In each model, TYRA-300 treatment increased nasoanal length and tibia and femur length. In the two FGFR3-altered models, TYRA-300–induced growth partially restored the disproportionality of long bones. Histologic analysis of the growth plate in Fgfr3Y367C/+ mice revealed that TYRA-300 mechanistically increased both proliferation and differentiation of chondrocytes. Importantly, children with ACH can experience medical complications due to foramen magnum stenosis, and TYRA-300 significantly improved the size and shape of the skull and foramen magnum in Fgfr3Y367C/+ mice. Spinal stenosis is also a frequent complication, and TYRA-300 increased the lumbar vertebrae length and improved the shape of the intervertebral discs in both models. Taken together, these studies demonstrate that the selective FGFR3 inhibitor TYRA-300 led to a significant increase in bone growth in two independent FGFR3-driven preclinical models as well as in wild-type mice.
Authors
Jacqueline H. Starrett, Clara Lemoine, Matthias Guillo, Chantal Fayad, Nabil Kaci, Melissa Neal, Emily A. Pettitt, Melissandre Pache, Qing Ye, My Chouinard, Eric L. Allen, Geneviève Baujat, Robert L. Hudkins, Michael B. Bober, Todd Harris, Ronald V. Swanson, Laurence Legeai-Mallet
Figure 2
TYRA-300 increases long bone length through modulation of the growth plate in the
