Grant Award Details
To develop therapeutically useful cells from hiPSCS, including antigen-specific T cells for adoptive immunotherapy, HSCs for bone marrow transplants, and whole organs (pancreas, liver).
Grant Application Details
- Generation of functional cells and organs from iPSCs
The development of induced pluripotent stem cell (iPSC) technology may be the most important advance in stem cell biology for the future of medicine. This technology allows one to generate a patient’s own pluripotent stem cells (PSCs) from skin or blood cells. iPSCs can then be reprogrammed to multiply and produce high quality mature cells for cell therapy. Because iPSCs
are derived from a patient's own cells, therapies that use them will not stimulate unwanted immune reactions or necessitate lifelong immunosuppression. If organs can be generated from iPSCs, many patients with organ failure awaiting transplants will be helped. The goal of this project is to further develop iPSC technology to bring about personalized regenerative medicine for treating intractable diseases such as cancers, viral infections, genetic blood disorders, and organ failure. Specifically, we would like to establish three major core programs for generating from iPSCs: personalized immune cells; an unlimited supply of blood stem
cells; and functional organs.
First, we will generate iPSC-derived immune cells that kill viruses and cancer cells. Current immunotherapy uses immune cells that are exhausted (have limited ability to function and proliferate) after they multiply in a test tube. To supply active nonexhausted immune cells, iPSCs will be generated from a patient’s immune cells that target tumor cells and infections and then redifferentiated to mature immune cells with the same targets.
Second, we aim to develop iPSC technology to generate blood stem cells that replenish all blood cells throughout life. Harvesting blood stem cells from a leukemia patient for transplantation back to the patient after chemotherapy and radiation has been challenging because few blood stem cells can be harvested and may be contaminated with cancer cells. Alternatively, transplanting blood stem cells from cord blood or another person requires genetic matching to prevent immune reactions. However, generating blood stem cells from a patient’s iPSCs may avoid contamination with cancer cells, immune reactions, and
the need to find a matched donor. Furthermore, we aim to generate iPSCs from a patient with a genetic blood disease, correct the genetic defect in the iPSCs, and generate from these corrected iPSCs healthy blood stem cells that may be curative when transplanted back into the patient.
Lastly, we will try to generate from iPSCs not just mature cells, but organs for transplantation, to potentially address the tremendous shortage of donated organs. In a preliminary study, we generated preclinical models that could not develop pancreases. When we injected stem cells into these models, they developed functional pancreases derived from the injected cells and survived to adulthood. We hope that within 10 years, we will be able to provide a needed organ to a patient by growing it from the patient’s own PSCs in a compatible animal.
Cancer is the second leading cause of death, accounting for 24% of all deaths in the U.S. Nearly 55,000 people will die of the disease--about 150 people each day or one of every four deaths in California. In 2012, nearly 144,800 Californians will be diagnosed with cancer. We need effective treatment to cure cancer.
End-stage organ failure is another difficult disease to treat. Transplantation of kidneys, liver, heart, lungs, pancreas, and small intestine has become an accepted treatment for organ failure. In California, more than 21,000 people are on the waiting lists at transplant centers. However, one in three of these people will die waiting for transplants because of the shortage of donated
organs. While end-stage renal failure patients can survive for decades with hemodialysis treatment, they suffer from high morbidity and mortality. In addition, the high medical costs for increasing numbers of dialysis patients is a social issue. We need to find a way to increase organs that can be used for transplantation. In our proposed projects, we aim to use iPSC technology and recent discoveries to develop new methods for treating cancers,
viral infections, and organ failure. More specifically, we will pursue our recent discoveries using iPSCs to: (1) multiply person’s T cells that specifically target cancers and viral infections; (2) generate normal blood-forming stem cells that can be transplanted back into a patient to correct a blood disease (3) regenerate tissues and organs from a patient’s cells for transplantation back into that patient.
These projects are likely to benefit the state of California in several ways. Many of the methods, cells, and reagents generated by this research will be patentable, forming an intellectual property portfolio shared by the state and the institutions where the research is performed. The funds generated from the licensing of these technologies will provide revenue for the state, will help
increase hiring of faculty and staff (many of whom will bring in other, out-of-state funds to support their research), and could be used to ameliorate the costs of clinical trials--the final step in translation of basic science research to clinical use. Most importantly, this research will set the platform for stem cell-based therapies. Because tissue stem cells are capable of lifelong
self-renewal, these therapies have the potential to provide a single, curative treatment. Such therapies will address chronic diseases that have no cure and cause considerable disability, leading to substantial medical expenses and loss of work. We expect that California hospitals and health care entities will be first in line for trials and therapies. Thus, California will benefit economically and the project will help advance novel medical care.
- Nature (2019) Long-term ex vivo haematopoietic-stem-cell expansion allows nonconditioned transplantation. (PubMed: 31142833)
- Nat Commun (2019) Generation of pluripotent stem cell-derived mouse kidneys in Sall1-targeted anephric rats. (PubMed: 30723213)
- Sci Rep (2019) LIM homeobox 2 promotes interaction between human iPS-derived hepatic progenitors and iPS-derived hepatic stellate-like cells. (PubMed: 30765795)
- Cell Stem Cell (2019) Highly Efficient and Marker-free Genome Editing of Human Pluripotent Stem Cells by CRISPR-Cas9 RNP and AAV6 Donor-Mediated Homologous Recombination. (PubMed: 31051134)
- Exp Hematol (2018) Branched-chain amino acid depletion conditions bone marrow for hematopoietic stem cell transplantation avoiding amino acid imbalance-associated toxicity. (PubMed: 29705267)
- Science (2018) Changing concepts in hematopoietic stem cells. (PubMed: 30467158)
- Nat Methods (2018) Efficient scarless genome editing in human pluripotent stem cells. (PubMed: 30504872)
- Biomaterials (2018) Human iPS derived progenitors bioengineered into liver organoids using an inverted colloidal crystal poly (ethylene glycol) scaffold. (PubMed: 30149262)
- Stem Cell Reports (2018) Generation of Vascular Endothelial Cells and Hematopoietic Cells by Blastocyst Complementation. (PubMed: 30245211)
- Transgenic Res (2018) Mosaicism diminishes the value of pre-implantation embryo biopsies for detecting CRISPR/Cas9 induced mutations in sheep. (PubMed: 30284144)
- Sci Rep (2018) An interspecies barrier to tetraploid complementation and chimera formation. (PubMed: 30327488)
- Sci Rep (2018) Using patient-derived iPSCs to develop humanized mouse models for chronic myelomonocytic leukemia and therapeutic drug identification, including liposomal clodronate. (PubMed: 30367142)
- Cell Rep (2018) Integrated Stress Response Activity Marks Stem Cells in Normal Hematopoiesis and Leukemia. (PubMed: 30380403)
- iScience (2018) Intra-embryo Gene Cassette Knockin by CRISPR/Cas9-Mediated Genome Editing with Adeno-Associated Viral Vector. (PubMed: 30447647)
- Curr Opin Genet Dev (2018) Interspecies chimeras. (PubMed: 29859382)
- ACS Synth Biol (2018) Designing Motif-Engineered Receptors To Elucidate Signaling Molecules Important for Proliferation of Hematopoietic Stem Cells. (PubMed: 29920201)
- J Hepatol (2018) Chimeric liver transplantation reveals interspecific graft remodelling. (PubMed: 30031887)
- Cell Stem Cell (2018) Large-Scale Clonal Analysis Resolves Aging of the Mouse Hematopoietic Stem Cell Compartment. (PubMed: 29625072)
- Stem Cell Reports (2018) Imaging-Based Screen Identifies Laminin 411 as a Physiologically Relevant Niche Factor with Importance for i-Hep Applications. (PubMed: 29478892)
- Cell Stem Cell (2018) Spred1 Safeguards Hematopoietic Homeostasis against Diet-Induced Systemic Stress. (PubMed: 29706577)
- Cell Stem Cell (2018) iPSC-Derived Organs In Vivo: Challenges and Promise. (PubMed: 29304339)
- Annu Rev Cell Dev Biol (2017) Lessons from Interspecies Mammalian Chimeras. (PubMed: 28806099)
- Sci Rep (2017) CRISPR/Cas9 microinjection in oocytes disables pancreas development in sheep. (PubMed: 29234093)
- Stem Cell Reports (2017) In Vivo Generation of Engraftable Murine Hematopoietic Stem Cells by Gfi1b, c-Fos, and Gata2 Overexpression within Teratoma. (PubMed: 28943250)
- Nature (2017) Interspecies organogenesis generates autologous functional islets. (PubMed: 28117444)