The use of stem cells or stem cell-derived cells to treat disease is one important goal of stem cell research. Major human illnesses, such as amyotrophic lateral sclerosis (Lou Gehrig’s disease), Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, diabetes, and macular degeneration represent opportunities where stem cell-based therapies may help patients. A second, important use for stem cells is the creation of cellular models of human development and disease, critical for uncovering the molecular and cellular roots of illness and testing new drugs. However, a major limitation in achieving these goals is the difficulty in manipulating the genes of human stem cells. Existing means of generating genetically modified stem cells are not ideal, as they do not preserve the normal gene regulation, are inefficient, and insert foreign genetic sequences.
For the promise of human stem cells to be realized, we must develop the tools to shape their properties. We have developed and extensively tested a method of genetically modifying mouse embryonic stem cells that is much more efficient than traditional methods. We propose to adapt this approach for use with human embryonic stem cells so that these cells can be better understood and harnessed for modeling, or even treating, human diseases. This approach seeks to overcome existing barriers to both basic and translational research using stem cells, and will improve and accelerate diverse aspects of biomedical research and fundamentally enhance the research enterprise.
Drawing upon our previous experience generating and genetically modifying mouse stem cells, we will create a resource of easily modified human stem cells, will integrate our technology with other resources, and will provide the research community with open access to these reagents and techniques. These stem cells will thus represent a large, unique public domain source of genetically modifiable human stem cells accessible to all researchers.
Although human stem cells hold the potential to generate new understanding about human biology and new approaches to important human diseases, the inability to efficiently and specifically modify stem cells limits the pace of current research. Presently, there is no safe means of changing human stem cell genes compatible with the use of the stem cells in human therapies. This proposal seeks to develop new genetic tools to allow for the tractable manipulation of human stem cells. By accelerating diverse other stem cell research projects, these tools will enhance the scientific, therapeutic, and economic development of California.
The ability to engineer specific genetic changes in human stem cells will be useful for widespread applications including the creation of models of early human development, replacement cells for personalized therapies, reporter lines for stem cell-based drug screens, and disease-associated mutations to explore the cellular bases of human illness. Additionally, the creation of a resource of manipulable stem cells will provide the larger research community with the tools to tailor stem cell genes for purposes beyond those envisioned here. Thus, the technology developed in this project will spur the research endeavors of the stem cell community in both the public and private arenas, contributing to economic growth and new product development. This research will increase biological and medical understanding and may promote the development of safer and more effective means of controlling embryonic stem cells. This project will also train students and postdoctoral scholars in human stem cell biology, who will contribute to the economic and research prowess of California.