Human embryonic stem cells, also known as pluripotent stem cells, are recognized as a valuable tool for advancing our knowledge of human development and biology, and also for their potential in regenerative medicine. Recently, new embryonic stem cell derivation technology has allowed scientists to derive the equivalent of human embryonic stem cells from adult cells, rather than from human embryos. This important advance allows for the possibility of eliminating the problem of immune system rejection of transplanted cells.
The use of embryonic stem cells, because they have thus far been derived from human embryos, is controversial. Recent technical innovations, however, have shown that there are now new opportunities for scientific progress with human pluripotent stem cells obtained from sources other than human embryos. Studies using human skin cells have shown that these skin cells can be directly reprogrammed back to their embryonic stem cell state without going through an embryonic state; thus, no embryos are created or destroyed using this new technology.
These human pluripotent stem cells obtained from skin have been termed induced pluripotent stem cells (iPSCs) as they have been induced by the forced expression of four human protein factors introduced into these skin cells using viruses. iPSC technology holds the promise that iPSCs can be derived from an individual's skin cells and from this state be triggered to form heart, brain and other cell types required for regenerative repair. As these cells may be derived from an individuals own skin and transplanted back into the same individual, the derived repair cells are likely recognized as self and thus unlikely subject to immune rejection.
Currently, the iPSC technology is unsuitable for use in humans as the viruses used to express the four factors required to induce the formation of the iPSC become part of DNA of the cell and are closely associated with causing cancer or other life-threatening diseases. Here, we propose a study to side step this difficulty by using a novel reagent to actively express the same four factors expressed in the virus-derived iPSCs but without the use of virus. Introducing active proteins into the cell in a non-integrative fashion helps eliminate the risk of cancer. When successful, the iPSCs derived using this technology will be safe for use in humans and this will allow a faster movement of successful patient-derived stem cell therapies into the clinic.
Statement of Benefit to California:
Human induced pluripotent stem cells (iPSCs) derived from differentiated human adult tissue cells following viral-driven expression of a small number of “reprogramming factors” are a monumental discovery. The possibility of translating iPSC technology to patient-derived stem cell therapy is nothing short of revolutionary and is of immediate benefit to every Californian and, indeed, all of humankind. This proposal will apply pre-existing, California-invented technology, in the form of a novel reagent to deliver the same active “reprogramming factors” directly to the nucleus of fibroblast cells. The resulting iPSCs will be suitable for clinical use as they are directly derived from the active proteins in the absence of cancer-associated viruses. This project is highly relevant to the goals of CIRM, and will result in the removal of a major block in the translation of iPSC technology to the clinic, namely the presence of random integrative cancer-causing viral sequences in the genome. The safe induction of patient-specific iPSCs will allow safe, effective and immune-tolerated stem cell therapies for the people of California and the world. This successful technology will have an immense economic benefit to California and illustrate that the people of California were justified in their support of stem cell research and have helped propel this research into the clinic for Californians and the world.