Animal models of Chiari malformation types 1 and 2: Mechanistic insights and translational challenges

Abstract

Chiari malformation (CM) types 1 and 2 are common congenital hindbrain disorders characterized by varying degrees of cerebellar herniation and association with neural tube defects. Knowledge of CM pathogenesis has thus far relied on preclinical animal models. Here, we provide a comprehensive review of animal models (genetic, teratogen-induced, surgical, and spontaneous) of CM1 and CM2, highlighting their construct validity, pathophysiological insights, and translational relevance. Genetic models exhibit defects in cranial base development, cerebrospinal fluid (CSF) flow, and neural tube closure. Teratogenic and surgical models have been informative for understanding the consequences of CSF leakage and validating prenatal treatments, especially in fetal sheep and chick embryos. Spontaneous models in dogs, cattle, and primates have offered complementary insights but the heterogeneity arising from species-specific differences obscures further understanding. Despite these advances, translational challenges persist, including species-specific differences in skull anatomy, CSF physiology, and symptomatology. We highlight the need for a patient-first approach, emphasizing the translational importance of large-scale gene discovery research in human patients to inform and prioritize dowstream functional investigations in animal models to enhance mechanistic understanding and support the development of etiology-specific therapies for CM.