PROJECT SUMMARY This application is being submitted in response to Notice of Special Interest (NOSI) identified as NOT-CA-24-029. High-grade Spinal Cord Glioma (SCG) is an orphan disease that results in significant morbidity and mortality, with no effective treatment options available. Despite significant advances in our knowledge of the disease process, there have unfortunately been limited changes to the clinical outcomes. In part, this represents the malignant nature of a disease that is refractory to the standard of care. On the other hand, this raises the question of the translational value of existing preclinical animal models, especially from a surgical standpoint – where widely scalable large animal models of SCG were previously unavailable. To this end, we have begun to address this gap in the field by developing a minipig SCG model. Through lentiviral targeting of the well implicated RTK/RAS/PI3K and p53 pathways, our preliminary data demonstrates the induction of high-grade astrocytoma with histopathologic, radiologic, and transcriptomic characterization in 100% of minipigs. Consequently, we posit that the next steps to advancement of this model system are to modulate tumor phenotype and to demonstrate its utility in a directly translatable surgical application. In the Parent Award, we will begin by evaluating the induction of SCG by targeting common genetic lesions implicated in the human disease including PDGFB, P53, CDKN2A, EGFR, and PTEN (AIM 1). In parallel, we will apply our existing minipig SCG model (AIM 2) to perform the first intra-tumoral convection enhanced delivery (CED) study for SCG in a large animal. In this Supplement, we plan to establish a low-grade glioma minipig model with the IDH mutation for potential therapeutic application, followed by the characterization of the tumor microenvironment. The outcome of our study will yield preliminary data for establishing a new LGG minipig model in the brain that characterizes the spread and evolution of IDH-relevant tumors, offering robust representations of human biology in a system that mimics the lifespan and anatomy of human disease.