Development of a Genetically Engineered Porcine Model of Rhabdoid Tumor Predisposition Syndrome Type 1 (RTPS-1).
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Background and Objectives: Among CNS malignancies arising in infancy, ATRT stands out as the most frequently diagnosed in children younger than six months. Disruption of the SMARCB1 gene underlies the overwhelming majority of cases. Progress toward effective treatment has been hampered by two persistent challenges. Current mouse models, while informative, fall short of reproducing the full clinical and biological picture of human ATRT, and their ability to predict therapeutic outcomes in patients remains uncertain. Compounding this, the rarity of the disease makes it difficult to assemble patient cohorts of sufficient size for meaningful clinical trials. At the molecular level, germline loss of SMARCB1 exons 4 and 5 has emerged as a particularly penetrant predisposing event, with affected individuals presenting at an earlier age than those harboring other mutation types. The porcine SMARCB1 gene offers a compelling basis for translational modeling as its protein product is identical to the human ortholog at every amino acid position across isoforms, a degree of conservation that exceeds what is seen in the mouse. Methods: Thus, we hypothesized that germline deletion of exons 4 and 5 would predispose heterozygote swine to ATRT development. In this manuscript, we describe the creation of an ATRT porcine model through a CRISPR/Cas9 mediated gene-editing approach. Results: 15 piglets were produced, two of which had confirmed SMARCB1 targeted excisions. However, none developed tumors. To induce further tumorigenicity, one pig with confirmed exons 4 and 5 excision was crossed with a pig with TP53 exon 2 truncation. In total, 11 piglets were born, of which one contained the original excision without a TP53 mutation. This piglet developed a spinal mass at the T1 level. Conclusion: To our knowledge, this is the first ATRT porcine model ever developed and provides proof-of-concept feasibility for large animal modeling of SMARCB1-deficient rhabdoid tumors. These findings support the continued development of porcine RTPS-1 models toward preclinical application.