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Retinoblastoma is a pediatric eye tumor in which bi-allelic inactivation of the  Retinoblastoma 1  ( RB1 ) gene is the initiating genetic lesion. Although recently curative rates of retinoblastoma have increased, there are at this time no molecular targeted therapies available. This is, in part, due to the lack of highly penetrant and rapid retinoblastoma animal models that facilitate rapid identification of targets that allow therapeutic intervention. Different mouse models are available, all based on genetic deactivation of both  Rb1  and  Retinoblastoma-like 1  ( Rbl1 ), and each showing different kinetics of retinoblastoma development. Here, we show by CRISPR/Cas9 techniques that similar to the mouse, neither  rb1  nor  rbl1  single mosaic mutant  Xenopus tropicalis  develop tumors, whereas  rb1 / rbl1  double mosaic mutant tadpoles rapidly develop retinoblastoma. Moreover, occasionally presence of pinealoblastoma (trilateral retinoblastoma) was detected. We thus present the first CRISPR/Cas9 mediated cancer model in  Xenopus tropicalis  and the first genuine genetic non-mammalian retinoblastoma model. The rapid kinetics of our model paves the way for use as a pre-clinical model. Additionally, this retinoblastoma model provides unique possibilities for fast elucidation of novel drug targets by triple multiplex CRISPR/Cas9 gRNA injections ( rb1  +  rbl1  +  modifier gene ) in order to address the clinically unmet need of targeted retinoblastoma therapy.

CRISPR/Cas9 mediated knockout of rb1 and rbl1 leads to rapid and penetrant retinoblastoma development in Xenopus tropicalis