MODL-13. GENETICALLY ENGINEERED PIG MODEL OF RHABDOID TUMOR PREDISPOSITION SYNDROME-1

Abstract

Atypical teratoid/rhabdoid tumor (AT/RT) is the most common malignant CNS tumor of children below 6 months of age. The majority of AT/RT demonstrate genomic alterations in the SMARCB1 gene. There are two major hurdles in the development of safe and effective treatments for AT/RT: first, the mouse models do not fully recapitulate the disease seen in patients and their predictivity of clinical efficacy is still unproven. Second, due to a small patient population, the ability to recruit enough patients for clinical trials is challenging. Genetic studies have demonstrated that germline deletion of SMARCB1 exons 4 and 5 predisposes to AT/RT at an early age. Comparison of human, swine, and mouse SMARCB1 genes show similarities in gene and protein structure, with 100% amino acid identity between swine and human SMARCB1 isoforms. Thus, we hypothesized that germline deletion of exons 4 and 5 will predispose heterozygote swine to AT/RT development. SMARCB1+/- founder pigs are obtained using a CRISPR/Cas9 mediated gene-editing of conventional crossbred swine embryos, followed by embryo transfer into female swine surrogates. They are evaluated for clinical criteria used to diagnose AT/RT and by MRI at 6, 12, and 24 months of age, followed by histopathology and molecular analysis of the tumors as they are detected. Generating a large animal model of AT/RT would represent a breakthrough in the field from a genomic, pathophysiologic, pre-clinical and therapeutic perspective.