The proposed research project aims to solve a key bottleneck in the use of human embryonic stem cells, and induced pluripotent stem cells for the regeneration and replacement of diseased or damaged tissues. This bottleneck is the potential of the transplanted stem cells to develop into a type of tumor called a teratoma, or teratocarcinoma. It is essential to overcome this obstacle before stem cell therapy becomes acceptable for human use.
Stem cells and cancer cells have some common properties. Both can replenish themselves indefinitely, and can potentially grow in different parts of the body. Before they are administered to patients, stem cells must be forced in the laboratory to turn into more mature cells that are programmed to become neurons, heart cells, beta cells of the pancreas, and other differentiated cell types. The mature cells, unlike the stem cells, do not grow indefinitely, but rather can replace a specific function that is defective in disease.
But what happens if some of the stem cells remain immature, despite our best efforts? They may begin to grow out of control, with potentially disastrous consequences. Hence, we must have a way to eliminate any residual embryonic stem cells before they are administered to patients. We also need safe and effective drugs that can prevent teratoma formation in humans, and treat the disease.
The team of investigators working on this research project aim to exploit a fundamental difference between embryonic stem cells and more mature cells. The survival of the embryonic stem cells depends upon the continued activity of an enzyme called mTOR. In contrast, the inhibition of mTOR does not cause the death of mature cells. One of our industry collaborators has developed an ultrapotent drug that inhibits mTOR, and is well tolerated when tested in mice. In preliminary studies, this agent destroyed embryonic stem cells at concentrations that did not harm mature cells. This compound was more effective than rapamycin, which partially inhibits mTOR.
We have also discovered a new drug that blocks a biochemical pathway called Wnt, that embryonic stem cells need to interact with their environment. This agent may have the ability to restrain the growth of embryonic stem cells in the body, without injuring important tissues and organs.
With these simple but powerful drugs, the project team aims to develop a practical protocol to purge any residual embryonic stem cells or induced pluripotent stem cells from tissue culture, without injuring the function of the mature, differentiated stem cells that are needed for treatment. The investigators also aim to demonstrate that the mTOR and Wnt inhibitors can effectively prevent teratoma formation in vivo, and can destroy any tumors that may develop.
The interactive group of scientists and physicians that are participating in this proposal have decades of experience and success in bringing molecules from the laboratory to the clinic.
Statement of Benefit to California:
Stem cell therapy has the potential to revolutionize the treatment of many common diseases that afflict the citizens of the State California. Alzheimer’s disease, diabetes, heart failure, anemia and arthritis are just a few of the illnesses that could potentially be treated. Responding to this need, the citizens of the State of California have dedicated billions of dollars to human stem cell research. For the investment to realize expectations, the supported scientists and physicians must develop stem cell remedies that are not only efficient, but are also devoid of dangerous side effects.
Stem cells can regenerate themselves indefinitely. For this reason, stem cells have the potential ability to grow and spread in the body, causing tumors called teratomas or teratocarcinomas. Indeed, teratoma formation has been observed in experimental models. Therefore, it is absolutely essential that we develop tools to prevent and to treat this potentially life-threatening complication of stem cell therapy. Otherwise the deployment in the clinic of the new stem cell treatments could be set back for years, at enormous cost. Every effort must be made to assure that future clinical trials of stem cell therapies offer adequate safeguards to patients.
The team of investigators in the proposed CIRM Early Translational Research Grant aim to produce a highly effective drug regimen, that can substantially reduce the possibility of teratoma formation, and that can eliminate any teratomas that occur. The research focuses on drugs, rather than large molecules, because drugs are more easily integrated into the practice of medicine. Preliminary experiments strongly suggest that this goal can be achieved within a few years.
The benefits of the proposed research to the State of California and to its citizens will be multiple. It will accelerate the pace of stem cell research, by helping to overcome a major obstacle to clinical trials. It will reduce the cost of stem cell therapeutic development, by providing a clear and rapid protocol for safety studies. Of greatest importance, it will protect the citizen-patients of the State of California, whose disease burden we aim to lessen.