Early Translational I
ICOC Funds Committed:
Transplantation of somatic stem cells (SCs) can be beneficial for patients with a multitude of degenerative conditions. However, the use of somatic stem cells has several disadvantages: 1) incompatibility of donor and host cells; 2) restricted differentiation potential; and 3) only limited quantities can be obtained from adult donors or neonatal tissues or by in vitro expansion. In contrast, embryonic stem cells (ESCs) are capable of developing into all tissues in the body and can be expanded ad infinitum. Thus, ESCs may serve as an excellent, alternative source of transplantable cells for regenerative medicine. However, similar to SCs, the use of ESCs produced conventionally using in vitro fertilization will be limited by host-graft rejection. Experimental approaches designed to avoid this outcome involve the use of retroviral vectors and the introduction of exogenous DNA (induced pluripotent stem cells, iPSCs). Another option is the use of somatic cell nuclear transfer (SCNT) to generate patient specific, histocompatible ESCs in a process referred to as therapeutic cloning (TC). While TC has not yet been accomplished in humans, recent success has been achieved in a preclinical model using a novel protocol for SCNT. Here, we propose to adapt this novel patented technology with a current efficiency of 10% in preclinical models to the generation of human, patient-specific, SCNT-ESCs and to compare their therapeutic potential to genetically related iPSCs.
Statement of Benefit to California:
The concept of stem cell based therapy implies that damaged tissues can be repaired by tissue-specific stem cells that generate mature, functionally active progeny. However despite obvious progress in the somatic stem cell transplantation approach, there are obstacles in effective stem cell-based therapy, namely a shortage of HLA-matched donors and technical limits on the in vitro expansion of somatic stem cells. In addition, the use of immunosuppressive drugs often results in severe site effects in these patients. Thus, alternative sources for transplantable cells are needed, and human histocompatible, pluripotent stem cells (PSCs) generated by somatic cell nuclear transfer (SCNT) theoretically represent an excellent source. Recently, a novel protocol for SCNT in large animal models was established with a 10% efficiency rate. An important aspect of this technology is that it has been patented and licensed by our California based company, thus providing a basis for further commercial development. Importantly, we will use the same donor fibroblasts to generate inducible PSCs (iPSCs) using viral-based and non-viral-based methods. Thus, we will create triads of genetically related PSCs, but derived by different methods to compare their therapeutic potential. These genetically-related triads of PSCs will be subjected to genetic, cytogenetic, epigenetic and potency analyses setting the stage for preclinical evaluation. Eventually benefits generated by the use of such cells in regenerative medicine should benefit all people but Californians will also profit from the generation of novel products (i.e. cell lines and media kits) commercially available to clinical, academic and for-profit research laboratories and from the regional experience and expertise in regenerative medicine.