Developing second generation SCID pig models: filling the gaps to improve translation of therapeutics in regenerative medicine

Iowa State University, Ames IA

Investigators

Linked publications, trials & patents

Abstract

Project Summary/Abstract: The promise of stem cell therapies has not been fully realized, due in part to a paucity of appropriate pre-clinical models. The pig is an excellent model of human biology, due to similarities of size, physiology, and genetics, and in some cases may be superior to rodent models, which often fail to provide data which effectively translates to human clinical trials. Thus, pig models that more accurately model humans are critically needed to improve research outcomes of regenerative medicine therapeutics and maximize safe translation to the clinic. As SCID pig models show promise in xenograft studies, this establishes further needs for humanized pigs as second-generation models and improved methods to routinely rear immunodeficient pigs for measurement of survival, safety, and potential efficacy of implanted therapeutic cells. We are focused on generating such new knowledge and demonstrating SCID pig use in preclinical regenerative medicine research. We have developed biocontainment facilities and protocols to raise several genetic lines of SCID pigs. We have demonstrated inability to reject xenografts through successful engraftment with human induced pluripotent stem cells (iPSC), cancer cell lines, and human skin. We have generated both SCNT-based and zygotic mutagenesis-based (non-cloned) RAG2-IL2RG models and have successfully demonstrated partial human immune system development in these pigs. We have also demonstrated engraftment and function of human iPSC-derived cardiomyocytes into the SCID pig heart. Thus we have taken pioneering steps to establish a pig SCID model, but improvements in xenograft safety/efficacy testing and humanization remain prerequisites to harness these research models for translational medicine. The specific aims of this application are to: 1.Determine the extent of human hematopoiesis in existing and newly developed SCID pig models and delivery systems; 2.Validate existing and novel SCID pig models for their value in preclinical safety and efficacy testing of cell and/or tissue xenografts; and 3.Refine second-generation SCID pig model management protocols and delivery systems of the SCID pig model at client locations. The rationale for the proposed research is that our outbred SCID pig may more accurately reflect how proposed stem cell derived therapies will function in humans compared to mice. This project is innovative because we will use an integrated approach to combine research on the model’s xenograft potential with research focused on protocols for improving the use of immunodeficient pigs, including humanization methods. We expect that the successful completion of this project will create genetic resources, data on xenograft and humanization rates, and improved husbandry. All of these will be highly desirable for SCID based modeling on the safety and efficacy of stem cell therapeutics. These unique resources are expected to have a significant impact in accelerating the translation of regenerative medicine research into the clinic.