Early Translational I
$5 165 028
Statement of Benefit to California:
The overall goal of this project is to develop safer human pluripotent cell lines for clinical use. The applicants propose to generate human induced pluripotency stem cells (iPSC) using an approach that combines the use of vectors with small molecules that stimulate the efficiency of iPSC production. As proof of concept, the applicants will use their new method to generate iPSC from type I diabetic patients, differentiate them into beta cell precursors and evaluate the ability of these transplanted cells to normalize glucose levels in diabetic mice. The applicants will determine the frequencies of teratoma formation in transplanted mice and also develop a genetic approach to efficiently eliminate undifferentiated iPSC during lineage-specific differentiation. In the final aim, this group will test the immunological consequences of autologous iPSC transplantation using a mouse model with a humanized immune system. This application addresses three bottlenecks to the development of iPSC for therapeutic use: potential oncogenicity of reprogramming factors delivered by integrating retroviruses, risk of teratoma formation from residual iPSC and the lack of a model to assess immunological responses to iPSC derivatives. The research plan, while ambitious, was well presented. Strong preliminary data including iPSC generation with the proposed methods and successful homologous recombination in hESC illustrate feasibility of the approach. As transplantation of pancreatic beta cell precursors has historically generated teratomas in vivo, use of this population to treat diabetes enables determination of both therapeutic effect and tumorigenicity. However, one reviewer felt these studies weren’t well integrated into the proposal. While full responsiveness of the T-cells matured in the model’s fetal thymus must be demonstrated, the development of a mouse model with a humanized immune system and the team’s inclusion of a leader in immunology with published experience generating such models did strengthen the proposal. Reviewers did note that the proposal would benefit from more discussion of pitfalls and alternative approaches. Reviewers universally praised the strength of the Principal Investigator’s (PI’s) experience in the field, publication record and the first rate assembly of collaborators for the project. The strong team makes success likely. Reviewers expressed concern that the PI may be overextended. In addition, the reviewers raised concerns about the proposal’s budget. Individual roles of the large number of investigators participating in the project, in particular that of the subcontractor responsible for the small molecule screens, should be more thoroughly defined and justified. The research environment is outstanding and available resources at the applicant’s institution are exceptional. This proposal, addresses three major bottlenecks to translating iPSC from novel research observation to therapeutic candidate: insertional mutagenesis, teratoma formation from residual undifferentiated cells and the lack of models to predict whether iPSC are truly immuno-privileged. Findings from this work should be applicable to the entire iPSC field. PROGRAMMATIC REVIEW During programmatic review, the Grants Working Group was instructed to consider the specific rank order of all applications in Tier I as an indicator of priority for funding. A motion was made to change the rank order of this application from 15 to 14 within Tier I as it addresses several bottlenecks of concern to CIRM’s mission. Reviewers felt that the proposed humanized mouse model is particularly important. The motion to change the rank order of this application carried.