Grant Award Details
User-friendly predictive molecular diagnostic assays for quality control of stem cell derivatives for transplantation and drug discovery
We will address these needs for stem cell translation by developing an RNAseq PluriTest2 version that incorporates measures of pluripotency, genomic stability, and safety of stem cells and derivatives. In addition, we will develop several "NeuroTests" for clinical applications, and PluriTest2 HTS for high throughput screening.
Human Stem Cell Use:
Embryonic Stem Cell
There is a critical need for better quality control analysis of stem cell-based therapeutic products and stem cell-derived cells used for other purposes, such as drug development and disease testing. Currently, PluriTest is the most popular method for assessing the pluripotency of human ES and iPSCs. We designed this application to be user-friendly and require no special expertise, which has encouraged researchers worldwide to substitute PluriTest for the teratoma assay, which requires laboratory mice and special skills. As of the fall of 2016, more than 14,500 datasets have been uploaded to our PluriTest website by 782 registered users in 29 countries. Our customers have requested a version of the assay that uses RNA sequencing data instead of the Illumina microarrays that have been used since we launched the application. Over the last year, we have collected a considerable amount of RNAseq data from our customers and colleagues, and have completed a beta version of PluriTest2 for RNAseq. We plan to release this application to beta users by the end of 2016. In addition, we have collected a large number of abnormal iPSC lines, which we will use to test the abilities of our new algorithm to detect abnormalities in genomic structure, an additional feature of PluriTest2 that we plan to implement during this grant award. Our long term goal is to make quality control assays available to all researchers and clinicians developing applications for pluripotent stem cells and their derivatives. To this end, we have collected multiple samples of iPSC and hESC-derived dopamine neurons from our lab and from others developing cell replacement therapies for Parkinson's disease. We are using these samples to develop DA-NeuroTest, the first of a family of user-friendly assays that will enable investigators to assure the safety of cell therapies. Other assays in this family will be used for quality control of neural derivatives used for high throughput screening and disease modeling, and for development of treatments for multiple sclerosis. We want every stem cell scientist to have access to tools that will assure that their cells are the correct type and are safe.
<p>The FDA is overwhelmed with applications for approval of "regenerative medicine" therapies. The failure of all clinical trials using fibroblasts called "mesenchymal stem cells" for heart disease therapy is particularly disappointing to regulators One of the disadvantages of using cells like MSCs is that the cells do not engraft, and their effects, if any, are transitory. This is also an advantage: because the cells do not remain in the body, the possibility of them become tumors is minimal. Another approach, durable engraftment of functional stem cell-derived cell types that are intended to replace degenerated or damaged cells in the body, is likely to be far more effective, but also raises concerns because the cells will remain in the recipient for years or even decades. Because the cells remain in the body, it is critical that the bar be raised for both safety and efficacy. </p><p>Raising the bar for FDA approval of stem cell therapies has been our goal for the last 12 years. </p><p>With CIRM and other funding, we have applied our expertise in genomics specifically to the problem of ensuring the safety and efficacy of durable cell therapies. This award enabled us to develop genomic tools to be certain that the cells engrafted are the right cells for treating the disease and that every effort has been made to make sure they will not form tumors. These genomic tools have enabled us to progress in development of an autologous dopamine neuron replacement therapy for Parkinson's disease, using patients' own induced pluripotent stem cells (iPSCs) for making neurons that will be effective and will be matched to the patient so they won't be rejected. Unfortunately, CIRM did not offer support for our clinical work, so we have obtained investment capital to move through the FDA approval process for this therapy. </p>
Grant Application Details
- User-friendly predictive molecular diagnostic assays for quality control of stem cell derivatives for transplantation and drug discovery
Three years ago, with help from CIRM funding, we developed an assay. This is a genomics-base diagnostic assay, similar to those now used for diagnosing cancers; but in our case, it is designed to analyze human ES and iPS cells. The assay is very simple to use; researchers use microarrays to profile the genes that are active in their cells. They upload the microarray data to the website, and in a few minutes they find out whether or not their cells are pluripotent. Our assay is replacing the old method for proving pluripotency, which involves producing tumors in animals. Our assay has been extremely popular, with 9,386 samples analyzed by 581 research groups in 29 countries so far. In this proposal, we plan to take the same concept and apply it to translational stem cell applications. Our new assay will allow researchers to easily detect DNA damage in their stem cells, and will enable the detection of undifferentiated or other abnormal cells (which potentially could form a tumor) in populations used for cell replacement therapy. We are also designing specific assays for quality control of neuronal cells to be transplanted to Parkinson's disease patients and for other neurological therapies. Finally, with our European partners, we will develop an assay for ensuring reliability of drug screening assays using stem cells. Our tools will greatly simplify translation of hESCs and iPSCs to the clinic.
Statement of Benefit to California:
California is at the leading edge of development of stem cell therapies to treat previously untreatable diseases. It is critical at this important stage, when treatments are being transferred from the lab to the clinic, that the cells used for therapy are carefully produced and qualified. Our project combines two of California's best scientific assets: genomics and stem cells. Our quality control assays for stem cell production are based on our long experience in genomic analysis of stem cells and development of genomics-based diagnostic tests. The assays will ensure that stem cells used for therapy are consistently of high quality. This will speed the development of stem cell therapies for Californians.
Source URL: https://www.cirm.ca.gov/our-progress/awards/user-friendly-predictive-molecular-diagnostic-assays-quality-control-stem-cell