To use human embryonic stem cells (hESC) for regenerative medicine, it is essential to develop methods to direct them to develop into specific cell types for clinical transplantation, such as pancreatic beta cells, nerve cells, hematopoietic stem cells, etc. Experimental research with hESC will seek to understand the mechanisms that control the processes by which hESC can be turned into specific cell types, and this knowledge can then be translated for the development of stem cell therapeutics. Techniques that allow new genes to be transferred into hESC will have many important experimental applications in studies of stem cell biology that will increase our knowledge of how stem cells develop into mature tissue cells. Gene transfer techniques may also have important clinical uses for the development of stem cell-based therapies. Stem cell therapies for patients with inherited disorders (e.g. sickle cell disease, cystic fibrosis, muscular dystrophy, immune deficiencies) will likely need a gene therapy component, so that the inherited gene defect can be corrected in the context of the patient's own genes (by moving the nucleus from the cell of a patient into hESC and correcting their genetic defect to produce “matching” and corrected tissue cells). Our central hypothesis is that gene transfer vectors capable of refined patterns of gene expression will provide enhanced capacity to manipulate hESC. We will develop novel gene delivery systems that can insert genes into hESC that will be expressed (”on”) specifically in different types of cells that develop from the hESC, such as cells along the stages of development from the embryo to pancreatic beta cells. The types of genes that will be studied include genes that can make the hESC grow and develop into specific cell types, or genes that produce a cell label (e.g. green fluorescent protein) to mark cells of specific types so that they can be isolated for studies or genes that can eliminate remaining hESC that have not fully developed into mature beta cells. By defining methods to effectively manipulate hESC, we will contribute both critical knowledge and experimental tools to the stem cell field. Moreover, the proposed studies will have direct clinical therapeutic applications for diabetes mellitus and other disorders that may be treated by stem cell therapies.
Development of methods for regenerative medicine using hESC will have wide-spread applications to improve the health and to provide novel, effective therapies for millions of Californians and tens of millions of people world-wide. Regenerative medicine may provide new treatments for diseases including diabetes mellitus, Parkinson’s disease, organ failure and injuries, inherited diseases and cancer and leukemia. The major challenge facing the field of regenerative medicine is to increase knowledge of the processes by which the mature cells of tissues (pancreas, brain, bone marrow, etc.) develop from stem cells, so that clinical approaches can be developed to produce cells suitable for transplantation. This Project will produce and apply novel tools for experimental studies of human embryonic stem cells (hESC) and for the development of clinical therapies using hESC. The central focus is on the development of gene delivery vectors that can transfer and express new genes in hESC, to influence their properties for research or for clinical purposes. These studies will help to advance the capacities for regenerative medicine. All scientific findings and biomedical materials produced from our studies will be publicly available to non-profit and academic organizations in California, and any intellectual property developed by this Project will be developed under the guidelines of CIRM to benefit the State of California.