The directed differentiation of human embryonic stem cells (hESCs) to high purity cell populations provides tremendous promise for drug discovery. Drug screening involves application of hundreds of thousands of novel drug candidates, one at a time, into a single plastic well containing a cell population, in order to identify one drug that has a beneficial effect on the cell population. This field is severely limited by a lack of high purity human cells to use in the screens. To date, drug candidates are tested on non-human cells, or immortalized human cell lines that have extremely little similarity to a normal human cell. This leads to errors in the identification of candidate drugs, which in turn leads to an immense wastage of money, time and resources, as well as an increased risk to humans participating in the first human tests of the candidate drug. Thus, differentiated human cells in high purity would provide ideal alternatives to the use of non-human cells or immortalized human cell lines for drug discovery, allowing highly relevant human data collection early in the screening process. We have developed a method to generate one human spinal cord cell type, motor neuron progenitors (MNPs), in large quantity (billions per week) and extremely high-purity (>98%) from hESCs. Motor neurons are lost in amyotrophic lateral sclerosis (Lou Gehrig's disease), spinal muscular atrophy, spinal cord injury, polio, and many other spinal cord diseases. Furthermore, we have seeded these high purity cells into 2 different models of conventional drug screening plates, containing either 96 or 384 wells, and validated a shipping system to ensure domestic or overseas shipment in a format that is ready to use. We have also developed methods to generate hESC-derived brain neuron cells and heart cells in large quantity (billions per week) and extremely high-purity (>98%), but we have not yet put these cells into drug screening wells. The overall goal of this program is to expand and optimize our 96 and 384 well drug screening programs to enable screening of millions of candidate drugs by the broader research and pharmaceutical communities. AIM 1 will optimize cell survival in the wells, consistency of the product, shipping, and quality control oversight for the application of MNPs to drug screening plates. AIM 2 will apply high purity human brain neuron cells to drug screening plates, then optimize as in AIM 1. AIM 3 will apply high purity human heart cells to drug screening plates, then optimize as in AIM 1. Ours is the first practical example of drug screening plates seeded with high purity human cells derived from any stem cell type. The optimization of this approach will provide an enabling hESC-based technology that will drastically decrease the hit to lead cycle time of drug discovery while providing a more relevant human safety profile.
Statement of Benefit to California:
The proposed research will benefit California by preserving and strengthening the State’s position as a leader in the field of stem cell therapeutics. Through the passage of Proposition 71 and subsequent establishment of the California Institute for Regenerative Medicine, the voters of California have identified stem cell research as a key area of focus for the state, with anticipated positive impacts including the creation of biotechnology jobs, attraction of leading researchers to California universities, creation of valuable intellectual property, and advancement of therapeutics beneficial to California residents. Our screening plate technology represents the first hESC-based drug discovery technology to have been commercialized in the world. Thus, this approach is the first to validate the State’s support of stem cell research and its application. This program has already led to job creation, tax revenue and other financial and reputation benefits; its advancement will lead to more. Additionally, hundreds of California-based companies and academic laboratories stand to benefit from this product if its development is successful.