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RL1-00645-1: Clinically Relevant iPS Cell Lines

Recommendation: Not recommended for funding

Public Abstract (provided by applicant)

Studies outlined in this proposal are designed to provide a platform for research and development of new clinically translatable iPS cell lines specifically addressing the shortcomings of current iPS procedures that impede potential translation of this approach for use in the clinic. Induction of pluripotent status in somatic cells by directed reprogramming in-vitro, induced pluripotent stem (iPS) cells, is of great potential significance for the generation of disease and patient specific cell lines and cell therapy (1,2,3). In addition to the need for genetic transduction of factors using retroviral vectors, this procedures requires selection of iPS host cells using genetic transduction of selectable markers followed by drug selection to isolate iPS cells. Although quite promising and revolutionary, to date iPS techniques share several main shortcomings which collectively impede potential translation of this approach for use in the clinic. Our long-term goal is to develop, tools, and cell lines that allow translation of iPS cells into therapies for the clinic. We propose to eliminate the need for genetic alterations of iPS cells, increase the efficiency of the process, and develop clinically applicable identification methodologies for iPS cells. Human iPS cells hold great potential for the generation of disease and patient specific cell lines and cell therapy. The current requirements for genetic alterations, however, are among major barriers for this potential. Accomplishing the specific aims outlined in this proposal will provide the foundation required to assess the possibility of generation of Human iPS cell lines by clinically relevant methodologies, eliminating the current impediments for translation of iPS cells into the clinic.

Statement of Benefit to California (provided by applicant)

Studies outlined in this proposal are designed to provide a platform for research and development of new clinically translatable induced pluripotent stem (iPS) cell lines specifically addressing the shortcomings of current iPS procedures that impede potential translation of this approach for use in the clinic. We propose to eliminate the need for genetic alterations of iPS cells, increase the efficiency of the process, and develop clinically applicable identification methodologies for iPS cells. Human iPS cells hold great potential for the generation of disease and patient specific cell lines, cell therapies and tissue regeneration, benefiting California’s pressing unmet need for patient customized cell lines that could be used for treatment of life threatening diseases and injuries. Accomplishing the specific aims outlined in this proposal will provide the foundation required to assess the possibility of generation of Human iPS cell lines by clinically relevant methodologies, eliminating the current impediments for translation of iPS cell lines into the clinic.

Review

This is a proposal based on optimization of the reprogramming procedure for induced pluripotent stem (iPS) cell lines, specifically addressing the shortcomings of current reprogramming procedures that hamper potential translation of this approach for use in the clinic. Specifically, the principal investigator (PI) proposes to screen 1600 compounds from a chemical library, individually and in combination, and about 15 polymeric matrix materials for their ability to reprogram human dermal fibroblasts into iPS cells, and to develop specific iPS cell markers for rapid identification of iPS cells. If successful, this study will provide a new method to generate clinically relevant iPS cells.

Reviewers agreed that the proposal addresses an important problem and that conceptually, the goal of circumventing retrovirus use for reprogramming is significant. On the other hand, in terms of feasibility, the review panel found that this application had several essential flaws that precluded them from recommending it for funding. The reviewers were concerned about the size of the chemical library; it remains to be justified why random screening of such a small library would lead to candidate compound(s) highly effective to reprogram human dermal fibroblasts. Furthermore, preliminary data were considered to be inconclusive, and the proposed screening approach was found to be highly risky at its current stage. It is also unclear how the team will test different combinations of chemical compounds, and the rationale for screening and the library design is not discussed either.

In addition to the chemical library, the PI proposes to screen about 15 biocompatible polymeric matrix materials for their ability to support iPS cell induction. The review panel expressed concern that some of the proposed materials have shown high cytotoxicity even for cell lines. Furthermore, the selection of compounds is random, very limited, and not justified. It is also unclear how the team will spot these compounds onto the proposed arrays. Overall, the feasibility of this method remains to be demonstrated. With regard to the development of specific iPS cell biomarkers, the reviewers felt that the proposed method is poorly defined; and all in all, it appears that there is no clear development path. Throughout the proposal, the PI has not carefully considered alternative tactics other than accessing other chemical libraries.

The following Working Group members had a conflict of interest with this application and were therefore recused from participating in review of, discussion of, and voting on the application:

• None