Preclinical modeling of Loeys-Dietz syndrome: insights into mechanisms and therapy

BACKGROUND: Loeys-Dietz syndrome (LDS) is a rare multisystemic connective tissue disorder characterized by aggressive aortopathy, skeletal, craniofacial, cutaneous and gastrointestinal manifestations. It is caused by pathogenic variants in genes encoding components of the transforming growth factor-beta (TGF-β) signaling pathway, including TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 and TGFB3. MAIN BODY: Preclinical modeling has been instrumental in elucidating LDS pathogenesis and informing therapeutic strategies. In this review, a comprehensive overview of available in vivo and in vitro models used to study LDS is presented. We critically evaluate the extent to which each model recapitulates the diverse LDS phenotypes and discuss their respective advantages and limitations. Attention is given to experimental design and variables that influence phenotype expression, including mouse genetic background, sex differences and variant-specific effects. We further synthetize insights gained from these models into the molecular and cellular mechanisms driving LDS, such as the TGF-β paradox, extracellular matrix dysregulation and immune activation. Lastly, we discuss current and emerging therapeutic strategies. CONCLUSION: The models described here highlight the critical role of preclinical modeling in advancing our understanding of LDS pathophysiology and therapy, outlining key considerations for future model development and translational application.