Development of Animal Models for Preclinical Safety Studies

A major concern in pluripotent stem cell (PSC)-based cell therapies is the incidence of tumor or cell mass consisting of immature or not fully differentiated cell mass generated from differentiation-resistant cells. These incidents could be caused by genetic abnormality or epi-genetic dysregulation ocurring during prolonged culture periods.In the case of iPSC-derived product, partial reprogramming or residual epigenetic memory would be special issues to consider. So far, we are unable to link the genetic abnormality or epigenetic dysregulation with the behavior of cells after transplantation in the microenvironment of tissue where transplanted. Therefore, a tumorigenicity test is indispensable as an in vivo safety test especially in first-in-human clinical studies. In this chapter, we discuss points to be considered in the selection of immuno-deficient rodents, number of rodents for one group for statistical analysis, doses of cells, selection of positive control cells, monitoring period and interpretation of test results, related to the design of tumorigenicity test from risk assessment perspective.