Achondroplasia: Current Disease-Modifying Therapies and Genome Editing Strategies

Abstract

Achondroplasia (ACH) is the most common non-lethal skeletal dysplasia and is caused in the vast majority of cases by a heterozygous gain-of-function variant in fibroblast growth factor receptor 3 (FGFR3, p.Gly380Arg). Hyperactive FGFR3 signaling constrains endochondral bone growth by suppressing growth-plate chondrocyte proliferation and hypertrophic differentiation. In the past decade, management has expanded beyond supportive care, and several mechanism-based interventions have shown disease-modifying effects in clinical studies. These include the activation of the NPR2/CNP axis with vosoritide and navepegritide and the pharmacologic attenuation of FGFR signaling with infigratinib, while extracellular biologics designed to modulate ligand–receptor interactions remain investigational. In parallel, gene-based approaches are increasingly discussed as routes toward the etiology-directed control of the causal driver, ranging from the cartilage-biased tuning of FGFR3 expression to variant-level genome editing concepts. Here, we synthesize the current therapeutic landscape, explicitly distinguish pathway-targeted disease modification from etiology-directed genetic strategies, and highlight the key translational barriers for gene-based approaches, including target-tissue delivery to the growth-plate, dose control and durability across development, redosing and immunogenicity constraints, and long-term safety.