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Identification and Characterization of Metastatic Factors by Gene Transfer into the Novel RIP-Tag; RIP-tva Murine Model
Published on: October 16, 2017
Development of a Genetically Engineered Porcine Model of Rhabdoid Tumor Predisposition Syndrome Type 1 (RTPS-1)
Brian Na1,2,3, C Dustin Rubinstein4, Jennifer J Meudt5
1Department of Head and Neck Surgery, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA.
Abstract:
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.
Insights
Researchers developed the first porcine model for Atypical Teratoid Rhabdoid Tumors (ATRT) by targeting the SMARCB1 gene. This new large animal model shows promise for studying ATRT and testing new treatments.
Area of Science:
- Oncology
- Genetics
- Animal Models
Background:
- Atypical Teratoid Rhabdoid Tumors (ATRT) are aggressive CNS malignancies primarily affecting infants, often linked to SMARCB1 gene disruption.
- Existing mouse models inadequately replicate human ATRT's clinical and biological aspects, limiting therapeutic outcome prediction.
- The rarity of ATRT complicates clinical trial patient cohort assembly, hindering treatment progress.
Purpose of the Study:
- To establish a large animal model for SMARCB1-deficient rhabdoid tumors using pigs, given the high conservation of the porcine SMARCB1 gene.
- To investigate the potential of germline deletion of SMARCB1 exons 4 and 5 in predisposing swine to ATRT development.
Main Methods:
- Utilized CRISPR/Cas9 gene editing to create a porcine model with targeted deletion of SMARCB1 exons 4 and 5.
- Crossed a pig with SMARCB1 exon deletion with one carrying a TP53 exon 2 truncation to enhance tumorigenicity.
- Monitored piglets for tumor development and genetic alterations.
Main Results:
- Two piglets exhibited confirmed SMARCB1 targeted excisions, but none spontaneously developed tumors.
- A subsequent cross resulted in piglets with SMARCB1 exon deletion; one developed a spinal mass, indicating tumor formation.
- This study reports the first porcine model for ATRT, demonstrating proof-of-concept for large animal modeling of these tumors.
Conclusions:
- The developed porcine model represents a significant advancement for studying SMARCB1-deficient rhabdoid tumors.
- This model offers a promising platform for preclinical research and therapeutic strategy evaluation for ATRT.
- Further development of this porcine model (RTPS-1) is supported for advancing ATRT preclinical applications.
