Path to the Clinic: Assessment of iPSC-Based Cell Therapies In Vivo in a Nonhuman Primate Model

Abstract

Summary Induced pluripotent stem cell (iPSC)-based cell therapies have a great potential for regenerative medicine, but are also potentially associated with tumorigenic risks. Current rodent models are not the optimal predictors of efficiency and safety for clinical application. Therefore, we developed a clinically relevant non-human primate model to assess the tumorigenic potential and in vivo efficacy of both undifferentiated and differentiated iPSCs in the autologous settings without immunosuppression. Undifferentiated autologous iPSCs indeed formed mature teratomas in a dose-dependent manner. However, tumor formation was accompanied by an inflammatory reaction. On the other hand, iPSC-derived mesodermal stromal-like cells formed new bone in vivo without any evidence of teratoma formation. We therefore show for the first time in a large animal model that closely resembles human physiology that undifferentiated autologous iPSCs form teratomas, and that iPSC-derived progenitor cells can give rise to a functional tissue in vivo.

Rhesus iPSC Safe Harbor Gene-Editing Platform for Stable Expression of Transgenes in Differentiated Cells of All Germ Layers

“…1 Frozen tissue sections were stained with anti-human CD19 (1:800, BD Biosciences) and Nestin (1:400, Neuromics) antibodies.…”

“…Nonhuman primate (NHP) induced pluripotent stem cells (iPSCs) have been valuable resources to model iPSC-based cell therapies in clinically relevant settings. [1][2][3][4] The close phylogenetic relationship of NHPs to humans, as well as their size, longevity, and the well-developed understanding of NHP physiology, makes these models very well suited to preclinical iPSC development. The ability to track derivation of tissues from iPSCs is necessary; thus, engineering NHP iPSCs to strongly and stably express reporter genes is desirable for monitoring of autologous or allogeneic transplanted cells in vivo.…”

Ten years of induced pluripotency: from basic mechanisms to therapeutic applications

“…As a proof-of-principle for tissue regeneration, she presented data for bone formation (Hong et al, 2014). The autologous transplant of iPSCs led to teratomas and an inflammatory reaction, whereas the transplant of mesodermal stromal-like cells derived from the iPSCs did not.…”

Induced Pluripotent Stem Cell Therapies for Degenerative Disease of the Outer Retina: Disease Modeling and Cell Replacement

“…79 Ensuring the purity of the final cell population by depletion of any residual pluripotent cell population is also crucial to avoid the risk of tumor formation. 80 …”