The overall goal of the proposed research is to develop tools to accelerate the translation of highly pluripotent human stem cell technologies to the clinic, including both induced pluripotent and human embryonic stem cells (hIPSC; hESC). To this end, the proposed studies will address the most serious translational bottleneck in the regenerative medicine field: safety. The critical safety concern is the potential of therapies to form a type of tumor called teratoma. Both academic and industry researchers must now rely upon a imperfect tool developed three decades ago to address these concerns: slow, expensive, and imprecise in vivo teratoma assays. Stem cell researchers also have few tools to enhance stem cell safety as there are no known teratoma inhibitors. The lack of optimal tools to measure and enhance the safety of stem cell therapies is a critical bottleneck for regenerative medicine.
Our solution to this problem is a new technology called in vitro teratoma assays. This “teratoma in a dish” technology consists of rapid, reproducible, in vitro teratoma assays that are 5,000 times less expensive per sample than the in vivo assay. We will use the in vitro teratoma assays not only to measure the safety of cells lines, but also to screen chemical libraries to discover a second type of powerful technology that enhances safety: teratoma inhibitors. In addition to measuring and enhancing safety, the in vitro teratoma assay technology can also be used to screen cell lines for pluripotency to identify bona fide hIPSC and hESC lines.
In vivo teratoma assay technology is a major weakness in the field. Its methodology has remained mostly unchanged for decades relying upon injecting stem cells under the skin of immunocompromised mice. As a result, testing large numbers of potential clinically valuable stem cell lines for safety is not feasible as it could require thousands of mice. In contrast, the in vitro teratoma technology would use less than a dozen plastic multi-well plates to achieve the same goal. Our “teratoma in a dish” technology has extremely broad clinical relevance, as any disease potentially treatable by regenerative medicine must first be safety tested.
The proposed research will also produce technology to enhance safety. We will use our in vitro teratoma assay system to screen for drugs that inhibit teratoma formation. These small molecules will serve as powerful tools to catalyze the advancement of pre-clinical studies to Phase I Trials. To date, the only safety measures available in the field are differentiation and cell sorting, but these are inadequate. We predict this new technology will lead to many new collaborative regenerative medicine research efforts as well.
When these studies are completed we will have produced powerful new tools for stem cell researchers to both measure and enhance stem cell safety, making the proposed studies transformative for regenerative medicine.
A major bottleneck in translating stem cell research into the clinic is the issue of safety. The two most promising types of stem cells for regenerative medicine, hESC and human iPS cells, both have the ability to cause teratoma and potentially other tumors. At present, the only method to assay the tumorigenicity of these cells involves slow and expensive murine model systems, so-called "in vivo teratoma assays". The proposed research will benefit California by producing a new technology whereby the tumorigenicity and hence safety of stem cell lines can be evaluated in a rapid, affordable manner using in vitro teratoma assays or "teratoma in a dish". This new technology will save a large amount of funds for California researchers working on regenerative medicine in the form of labor, supply, and animal care costs now associated with the in vivo teratoma assays. Per sample, our in vitro assays are 5,000 times cheaper than the traditional in vivo assays.
A second benefit of the proposed research is that it will identify drugs that can be used to enhance the safety of stem cells prior to their use in transplantation therapies. Currently there are no known potent inhibitors of teratoma formation. Identification of drugs that block teratoma formation will make clinical trials progress more rapidly and reduce costs, a great benefit to California. By enhancing safety, the drugs will also make regenerative medicine therapies more efficient and effective.