Development of Diagnostics to Assess Potential Teratoma Tumorigenicity in Human Stem Cell Derived Therapeutics

Funding Type: 
Tools and Technologies I
Grant Number: 
RT1-01069
Investigator: 
ICOC Funds Committed: 
$0
oldStatus: 
Closed
Public Abstract: 
The primary goal of this application is to utilize [REDACTED] ultra-sensitive genetic and epigenetic fingerprinting technologies to identify unique biomarkers that distinguish between teratoma and hES cells, which can be used to develop diagnostic tests that evaluate ES cells to ensure that they are teratoma-free and suitable for clinical applications. Biologic therapies derived from human stem cells through tissue regeneration and the targeted delivery of genetic material are expected to provide effectiv treatments for a wide range of medical conditions. However, the potential for in vivo stem cell tumorigenicity due to teratoma development represents one of the primary safety concerns noted in the recent FDA Guidance on Stem Cells and a key issue confronting the development of cellular therapies derived from human embryonic stem cells. The specific aims of proposed research addresses these tumorigenicity concerns by using [REDACTED] ‘s established collection of ultra-sensitive profiling technologies t develop fingerprints for identifying teratoma-specific biomarkers suitable for screening hES cell preparations to assess their safety prior to their use in clinical applications. To accomplish these goals, comprehensive fingerprints of promoter/ enhancer interactions, methylation, multiple histone modifications, mRNA profiling, and protein expression will be compiled in hES and teratoma cells using [REDACTED] ‘s proprietary ChIP-on-Chip, and Next Generation Sequencing based ChIP-Seq and mRNA profiling technologies in conjunction with [REDACTED] ‘s collection of antibodies to the entire family of mouse and human transcription factors (TF). This will include genome-wide profilin of factor interactions identified with promoter (H3K4me3, TAF250, and Pol II) and enhancer (H3K4me1) activation, in conjunction with promoter DNA Methylation mapping, as well as studies involving germ-line specific antibody profiling. The utility of these identified targets that distinguish between teratoma and hES cells will subsequently be validated by tracing the teratoma status in a pancreatic beta cell differentiation lineage. These studies will facilitate the identification of unique teratoma-speciic biomarkers that will enable development of diagnostic tests that allow for rapid determination of the presence of contaminating teratoma cells in potential clinical ES cell samples by integrating multi-level profiling data to provide a comprehensive view of the transcriptional and translational networks that are active in ES and teratoma cells.
Statement of Benefit to California: 
The proposed research will be of great value to the people of California in potentiating the safe use of hES cell therapies currently being developed as therapeutic treatments for a wide range of medical conditions. The FDA has recently identified potential stem cell tumorigenicity due to teratoma development as a major safety concern and a key issue confronting the development of cellular therapies derived from human embryonic stem cells. The research in this proposal will address these concerns by identifying teratoma and hES cell specific biomarkers which will be incorporated into diagnostic tests that can quickly assess the tumorigenicity potential of hES cell derived therapeutics, and consequently expedite the safe use of stem cell therapeutics within the California population.

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