Blood Disorders

Coding Dimension ID: 
278
Coding Dimension path name: 
Blood Disorders
Funding Type: 
Research Leadership 14
Grant Number: 
LA1_C14-08014
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$5 174 715
Disease Focus: 
Blood Disorders
Stem Cell Use: 
Adult Stem Cell
Public Abstract: 
Bone marrow and peripheral blood transplantation utilizing blood stem cells can provide curative treatment for patients with cancers and non-cancerous diseases of the blood and immune systems. Such treatments can be curative because the stem cells contained within the bone marrow or peripheral blood of healthy donors are capable of replacing the entirety of the patient’s blood system and providing a new immune system which can eradicate the patient’s cancer cells. The application of blood stem cell transplantation could be applied to a much larger population of patients if methods could be developed to expand blood stem cells in vitro or in vivo. This would be particularly beneficial for the broadened application of human cord blood transplantation for the many patients who lack an immune-matched sibling or unrelated donor. Furthermore, a method to expand human blood stem cells in vivo could be highly beneficial for the thousands of patients with cancer who require toxic chemotherapy which frequently results in decreased blood counts, infections and bleeding complications. A systemic treatment (i.e. a shot) which could cause blood stem cells to grow and produce more blood cells in patients could markedly improve patient’s outcomes after they receive such chemotherapy in the curative treatment of cancer. However, the development of treatments capable of inducing human blood stem cells to grow in the body has been very slow, in part due to a lack of understanding of the processes which govern blood stem cell growth in general. In my laboratory, we have developed mouse genetic models which allow us to discover new proteins produced in the bone marrow (the “soil” where blood stem cells reside) which make blood stem cells grow. We have recently discovered that 2 proteins are secreted by blood vessels within the bone marrow and cause blood stem cells to grow rapidly following damage with radiation. We are currently in the process of developing one of these into a growth factor that we can deliver to patients via injection as a means to cause their blood stem cells to grow after cord blood transplantation or following chemotherapy treatment for cancer. In this proposal, we will utilize our unique mouse models to discover the additional growth factors that make blood stem cells grow and we will perform pre-clinical studies to test whether these newly discovered growth factors can cause human blood stem cells to grow in vitro and in vivo. This proposal has the potential to generate new understanding of how human stem cells grow in vivo and to facilitate the development of new therapies which can regenerate human blood stem cells and the blood system as a whole in patients.
Statement of Benefit to California: 
My research program has both basic science and pre-clinical components which I believe will benefit California in several important ways: First, my basic research program will contribute new fundamental knowledge in stem cell biology which will benefit students, fellows and faculty. My research will also synergize with other campus laboratories and other centers in California and will lead to collaborations and accelerated translation of these discoveries for regenerative medicine. Second, my research program has the potential to directly benefit patients in California. We have already discovered two niche-derived proteins which promote hematopoietic stem cell regeneration in vivo and are focusing substantial efforts now to develop these proteins as therapeutics for Phase I clinical trials. For example, we are developing one of the HSC regenerative factors which we discovered for a Phase I clinical trial to test its efficacy as a systemic therapy to accelerate cord blood engraftment and hematologic recovery in adult cord blood transplant patients. This has literal potential benefit for patients since approximately 10% of cord blood transplant patients die from complications of graft failure or delayed hematologic recovery. In addition, patients with cancer who receive myelosuppressive chemotherapy can potentially benefit from systemic administration of [REDACTED] or other HSC regenerative factors that we discover to accelerate hematologic recovery after chemotherapy. If we are able to show that administration of such regenerative factors can accelerate hematologic recovery in patients after chemotherapy, then remission rates for cancer patients may increase via more effective delivery of curative chemotherapy on time and to completion. Third, my research will provide new intellectual property. These inventions from my laboratory will be available for licensure to biotech or pharmaceutical companies in California. I have experience with licensing inventions from my laboratory to biotech companies and am eager to see my future inventions licensed to accelerate development for regenerative medicine. Fourth, my research program will provide new jobs and professional opportunities. At present, my research program provides partial or complete funding for more than 30 employees internally and more than 30 employees at our partner institutions in academia and biotechnology. I will also bring substantial federal research funding with me to California and will be hiring new fellows, technicians and faculty promptly upon my arrival. Taken together, I am hopeful that my research program will have a major benefit for the scientific community of California, for patients who may benefit from treatments we are developing, for the biotechnology community via the development of new intellectual property and for the larger economy via the creation of many new jobs. I sincerely look forward to the opportunity to bring my program to California.
Funding Type: 
Alpha Stem Cell Clinics
Grant Number: 
AC1-07659
Investigator: 
ICOC Funds Committed: 
$8 000 000
Disease Focus: 
Blood Disorders
Blood Cancer
Cancer
HIV/AIDS
Solid Tumor
Stem Cell Use: 
Adult Stem Cell
Public Abstract: 
As the largest provider of bone marrow cell transplants in California, and the second largest in the nation, our institution has great expertise and an excellent record of safety in the delivery of stem cell treatments. We now propose to create the Alpha Clinic for Cell Therapy and Innovation (ACT-I) in which new, state-of-the-art, stem cell treatments for cancer and devastating blood-related diseases will be conducted and evaluated. As these experimental therapies prove to be effective, and become routine practice, our ACT-I Program will serve as the clinical center for delivery of these treatments. ACT-I will be an integral part of our Hematologic Malignancy and Stem Cell Transplantation Institute, placing it in the center of our institutional strengths, expertise, infrastructure and investment over the next decade. To move quickly once the CIRM award is made, ACT-I can be launched within our institution’s Day Hospital, a brand new, outpatient blood stem cell transplantation center opened in late 2013 with California Department of Health approval for 24 hour a day operation. This will ensure that ACT-I will have all the clinical and regulatory expertise, trained personnel, state-of-the-art facilities and other infrastructure in place to conduct first-in-human clinical trials and to deliver future, stem cell-based therapies for cancer and blood-related diseases, including AIDS. When our new Ambulatory Treatment Center is complete in 2018, it will double our capacity for patient visits and allow for expansion of the ACT-I pipeline of new stem cell products in a state-of-the-art facility. Beyond our campus, we operate satellite clinics covering an area that includes urban, suburban and rural sites. More than 17.7 million people live in this area, and represent some of the greatest racial and ethnic diversity seen in any part of the country. Our ACT-I is prepared to serve a significant, diverse and underserved portion of the population of California. CLINICAL TRIALS. Our proposal has two lead clinical trials that will be the first to be tested in ACT-I. One will deliver transplants of blood stem cells that have been modified to treat patients suffering from AIDS and lymphoma. The second will use neural stem cells to deliver drugs directly to cancer cells hiding in the brain. These studies represent some of the new and exciting biomedical technologies being developed at our institution. In addition to the two lead trials, we have several additional clinical studies poised to use and be tested in this special facility for clinical trials. In summary, ACT-I is well prepared to accommodate the long list of clinical trials and begin to fulfill the promise of providing new stem cell therapies for the citizens of California.
Statement of Benefit to California: 
California’s citizens voted for the California Stem Cell Research and Cures Act to support the development of stem cell-based therapies that treat incurable diseases and relieve human suffering. To achieve this goal, we propose to establish an Alpha Clinic for Cellular Therapies and Innovation (ACT-I) as an integral part of our Hematological Malignancies and Stem Cell Transplantation Institute, and serve as the clinical center for the testing and delivery of new, cutting-edge, cellular treatments for cancer and other blood-related diseases. Our institution is uniquely well-suited to serve as a national leader in the study and delivery of stem cell therapeutics because we are the largest provider of stem cell transplants in California, and the second largest in the country. According to national benchmarking data, our Hematopoietic Cell Transplantation program is the only program in the nation to have achieved survival outcomes above expectation for each of the past nine years. This program currently offers financially sustainable, research-driven clinical care for patients with cancer, HIV and other life-threatening diseases. CIRM funding will allow the ACT-I clinic to ramp up quickly, drawing upon institutionally established protocols, personnel and infrastructure to conduct first-in-human clinical trials for assessment of efficacy. As CIRM funding winds down, ACT-I will have institutional support to offer proven cellular therapeutics to patients. The lead studies at the forefront of the ACT-I pipeline of clinical trials focus on treatments for HIV-1 infection and brain tumors, two devastating and incurable conditions. These first trials are closely followed by a robust queue of other stem cell therapeutics for leukemia, lymphoma, prostate cancer, brain cancers and thalassemia. Our long list of proposed treatments addresses diseases that have a major impact on the lives of Californians. Thalassemia is found in up to 1 in 2,200 children born in California; prostate cancer affects 211,300 men, and HIV-1 infection occurs in 111,000 of our citizens. From 2008 to 2010, 6,705 Californians were diagnosed with brain cancers, 4,580 of whom died. In considering hematological malignancies during this same period, 2,800 patients were diagnosed with Hodgkin lymphoma (416 died), 20,351 with non-Hodgkin lymphoma (6,241 died), 13,358 with leukemia (6,961 died), 3,900 with acute myelogenous leukemia (2,972 died), 2,129 with acute lymphoblastic leukemia (648 died) and 4,198 with chronic lymphocytic leukemia (1,271 died). Standard of care fails in many cases; mortality rates for patients with hematological malignancies range from 25% to 76%. Successful stem cell therapeutics hold the promise to reduce disease-related mortality while improving disease-related survival and quality of life for the citizens of California, and for those affected by these diseases worldwide.
Funding Type: 
Strategic Partnership II
Grant Number: 
SP2-06902
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$6 374 150
Disease Focus: 
Blood Disorders
Pediatrics
Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 
β-thalassemia is a genetic disease caused by diverse mutations of the β-globin gene that lead to profoundly reduced red blood cell (RBC) development. The unmet medical need in transfusion-dependent β-thalassemia is significant, with life expectancy of only ~30-50 years despite standard of care treatment of chronic blood transfusions and iron chelation therapy. Cardiomyopathy due to iron overload is the major cause of mortality, but iron-overload induced multiorgan dysfunction, blood-borne infections, and other disease complications impose a significant physical, psychosocial and economic impact on patients and families. An allogeneic bone marrow transplant (BMT) is curative. However, this therapy is limited due to the scarcity of HLA-matched related donors (<20%) combined with the significant risk of graft-versus-host disease (GvHD) after successful transplantation of allogeneic cells. During infancy, gamma-globin-containing fetal hemoglobin protects β-thalassemia patients from developing disease symptoms until gamma globin is replaced by adult-type β-globin chains. The proposed therapeutic intervention combines the benefits of re-activating the gamma globin gene with the curative potential of BMT, but without the toxicities associated with acute and chronic immunosuppression and GvHD. We hypothesize that harvesting hematopoietic stem and progenitor cells (HSPCs) from a patient with β-thalassemia, using genome editing to permanently re-activate the gamma globin gene, and returning these edited HSPCs to the patient could provide transfusion independence or greatly reduce the need for chronic blood transfusions, thus decreasing the morbidity and mortality associated with iron overload. The use of a patient’s own cells avoids the need for acute and chronic immunosuppression, as there would be no risk of GvHD. Moreover, due to the self-renewing capacity of HSPCs, we anticipate a lifelong correction of this severe monogenic disease.
Statement of Benefit to California: 
Our proposed treatment for transfusion dependent β-thalassemia will benefit patients in the state by offering them a significant improvement over current standard of care. β-thalassemia is a genetic disease caused by diverse mutations of the β-globin gene that lead to profoundly reduced red blood cell (RBC) development and survival resulting in the need for chronic lifelong blood transfusions, iron chelation therapy, and important pathological sequelae (e.g., endocrinopathies, cardiomyopathies, multiorgan dysfunction, bloodborne infections, and psychosocial/economic impact). Incidence is estimated at 1 in 100,000 in the US, but is more common in the state of California (incidence estimated at 1 in 55,000 births) due to immigration patterns within the State. While there are estimated to be about 1,000-2,000 β-thalassemia patients in the US, one of our proposed clinical trial sites has the largest thalassemia program in the Western United States, with a population approaching 300 patients. Thus, the state of California stands to benefit disproportionately compared to other states from our proposed treatment for transfusion dependent β-thalassemia. An allogeneic bone marrow transplant (BMT) is curative for β-thalassemia, but limited by the scarcity of HLA-matched related donors (<20%) combined with the significant risk of graft-versus-host disease (GvHD) after successful transplantation of allogeneic cells. Our approach is to genetically engineer the patient’s own stem cells and thus (i) solve the logistical challenge of finding an appropriate donor, as the patient now becomes his/her own donor; and (ii) make use of autologous cells abrogating the risk of GvHD and need for acute and chronic immunosuppression. Our approach offers a compelling pharmacoeconomic benefit to the State of California and its citizens. A lifetime of chronic blood transfusions and iron chelation therapy leads to a significant cost burden; despite this, the prognosis for a transfusion dependent β-thalassemia patient is still dire, with life expectancy of only ~30-50 years. Our proposed one-time treatment aims to reduce or eliminate the need for costly chronic blood transfusions and iron chelation therapy, while potentially improving the clinical benefit to patients, including the morbidity and mortality associated with transfusion-induced iron overload.
Progress Report: 
  • Summary of progress
  • Our CIRM-funded effort aims to develop a treatment for beta-thalassemia. Beta-thalassemia is an inherited genetic disorder that is caused by mutations (changes in the DNA) in a gene called beta-globin. This gene produces a protein that forms hemoglobin in red blood cells that carry oxygen to through the body. In an individual with beta-thalassemia, beta-globin is not produced (or is made in dramatically reduced quantities), and so the person does not make enough healthy red blood cells. The treatment, which is essential for life in these patients, is repeated blood transfusions (typically once a month or more frequently). The transfusion of blood this frequently results in a dangerous condition called “iron overload,” which must be treated with costly drugs. In general, the quality of life of many people with beta-thalassemia is poor.
  • At present, there is only one cure, and that is to carry out a bone marrow transplant. This involves taking special cells from a healthy person called “hematopoietic stem cells” that give rise to blood cells for the whole of a person's life, and giving them to the patient so that they that they are now able to make healthy red blood cells for their lifetime. However, the cell donor must be an immunologic match to the patient and for many people with beta-thalassemia, such donors are not available.
  • Our approach to treating beta-thalassemia aims to genetically engineer a person’s hematopoietic stem cells (change the DNA inside the cell) to allow them to make healthy red blood cells using a technology that we have developed called "zinc finger nucleases,” or ZFNs. We plan to obtain stem cells from a beta-thalassemia patient, genetically engineer them by transiently exposing them to ZFNs, and then transplant them back into the same individual, making the patient their own donor. The genetic engineering is designed to replicate a situation observed in certain people with beta-thalassemia who have milder symptoms than others. Such patients have a much higher than average level of a “backup” form of beta-globin, called fetal globin, in their blood.
  • All people make fetal globin while in utero and after birth, but in infancy the levels of fetal globin decrease and the child begins to make adult beta-globin. It is at this stage that the symptoms of beta-thalassemia become evident. However, if person with beta-thalassemia has high level of fetal globin, they will be spared the severe effects of the disease.
  • We know that certain individuals who have an elevated level of fetal globin do so because they have a less active form of a gene called BCL11A that normally shuts down the production of fetal globin during infancy. Making use of this observation, our approach is to knock out BCL11A in a patient’s own stem cells, transplant them back into the patient to allow the production of fetal hemoglobin and, as a consequence, increase production of healthy red blood cells.
  • In order to test drugs in humans investigators must consult with the US Federal Drug Administration (FDA) and ultimately submit data about the investigational drug to various regulatory bodies including the FDA as part of Investigational New Drug (IND) application. This past year, we held a meeting with the Center for Biologics Evaluation and Research of the FDA known as a “pre-IND” and received useful guidance on issues that we should address in preparing the IND filing. We also presented our program to the Recombinant DNA Advisory Committee of the NIH (RAC); our proposed preclinical safety assessment program and plan for the phase I clinical trial received unanimous approval from the RAC.
  • Our work this year focused on two major deliverables that are necessary to achieve the goal of beginning a clinical trial of our approach. The first one relates to our ability to purify and efficiently genetically engineer a sufficient quantity of stem cells from a patient with beta-thalassemia. Working with healthy volunteers, and in a setting that is identical to the one we plan to use during our clinical trial, we have been able to consistently obtain sufficient quantities of hematopoietic stem cells to treat an individual with beta-thalassemia, and attain high levels of targeted genetic engineering in those cells.
  • As part of a preclinical safety assessment program, we have initiated and completed a series of studies to determine whether the genetic engineering we perform has any unforeseen untoward consequences in the cell. When we have completed this effort, we aim to file the IND application with the FDA before the end of the year and, pending FDA acceptance, initiate the phase 1 clinical trial in 2015.
Funding Type: 
Tools and Technologies II
Grant Number: 
RT2-02060
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 869 487
Disease Focus: 
Blood Disorders
Heart Disease
Liver Disease
Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
oldStatus: 
Active
Public Abstract: 
Purity is as important for cell-based therapies as it is for treatments based on small-molecule drugs or biologics. Pluripotent stem cells possess two properties: they are capable of self regeneration and they can differentiate to all different tissue types (i.e. muscle, brain, heart, etc.). Despite the promise of pluripotent stem cells as a tool for regenerative medicine, these cells cannot be directly transplanted into patients. In their undifferentiated state they harbor the potential to develop into tumors. Thus, tissue-specific stem cells as they exist in the body or as derived from pluripotent cells are the true targets of stem cell-based therapeutic research, and the cell types most likely to be used clinically. Existing protocols for the generation of these target cells involve large scale differentiation cultures of pluripotent cells that often produce a mixture of different cell types, only a small fraction of which may possess therapeutic potential. Furthermore, there remains the real danger that a small number of these cells remains undifferentiated and retains tumor-forming potential. The ideal pluripotent stem cell-based therapeutic would be a pure population of tissue specific stem cells, devoid of impurities such as undifferentiated or aberrantly-differentiated cells. We propose to develop antibody-based tools and protocols to purify therapeutic stem cells from heterogeneous cultures. We offer two general strategies to achieve this goal. The first is to develop antibodies and protocols to identify undifferentiated tumor-forming cells and remove them from cultures. The second strategy is to develop antibodies that can identify and isolate heart stem cells, and blood-forming stem cells capable of engraftment from cultures of pluripotent stem cells. The biological underpinning of our approach is that each cell type can be identified by a signature surface marker expression profile. Antibodies that are specific to cell surface markers can be used to identify and isolate stem cells using flow cytometry. We can detect and isolate rare tissue stem cells by using combinations of antibodies that correspond to the surface marker signature for the given tissue stem cell. We can then functionally characterize the potential of these cells for use in regenerative medicine. Our proposal aims to speed the clinical application of therapies derived from pluripotent cell products by reducing the risk of transplanting the wrong cell type - whether it is a tumor-causing residual pluripotent cell or a cell that is not native to the site of transplant - into patients. Antibodies, which exhibit exquisitely high sensitivity and specificity to target cellular populations, are the cornerstone of our proposal. The antibodies (and other technologies and reagents) identified and generated as a result of our experiments will greatly increase the safety of pluripotent stem cell-derived cellular therapies.
Statement of Benefit to California: 
Starting with human embryonic stem cells (hESC), which are capable of generating all cell types in the body, we aim to identify and isolate two tissue-specific stem cells – those that can make the heart and the blood – and remove cells that could cause tumors. Heart disease remains the leading cause of mortality and morbidity in the West. In California, 70,000 people die annually from cardiovascular diseases, and the cost exceeded $48 billion in 2006. Despite major advancement in treatments for patients with heart failure, which is mainly due to cellular loss upon myocardial injury, the mortality rate remains high. Similarly, diseases of the blood-forming system, e.g. leukemias, remain a major health problem in our state. hESC and induced pluripotent stem cells (collectively, pluripotent stem cells, or PSC) could provide an attractive therapeutic option to treat patients with damaged or defective organs. PCS can differentiate into, and may represent a major source of regenerating, cells for these organs. However, the major issues that delay the clinical translation of PSC derivatives include lack of purification technologies for heart- or blood-specific stem cells from PSC cultures and persistence of pluripotent cells that develop into teratomas. We propose to develop reagents that can prospectively identify and isolate heart and blood stem cells, and to test their functional benefit upon engraftment in mice. We will develop reagents to identify and remove residual PSC, which give rise to teratomas. These reagents will enable us to purify patient-specific stem cells, which lack cancer-initiating potential, to replenish defective or damaged tissue. The reagents generated in these studies can be patented forming an intellectual property portfolio shared by the state and the institutions where the research is carried out. 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. Only California businesses are likely to be able to license these reagents and to develop them into diagnostic and therapeutic entities; such businesses are at the heart of the CIRM strategy to enhance the California economy. Most importantly, this research will set the platform for future stem cell-based therapies. Because tissue stem cells are capable of lifelong self-renewal, stem cell therapies have the potential to be a single, curative treatment. Such therapies will address chronic diseases with no cure that cause considerable disability, leading to substantial medical expense. We expect that California hospitals and health care entities will be first in line for trials and therapies. Thus, California will benefit economically and it will help advance novel medical care.
Progress Report: 
  • Our program is focused on improving methods that can be used to purify stem cells so that they can be used safely and effectively for therapy. A significant limitation in translating laboratory discoveries into clinical practice remains our inability to separate specific stem cells that generate one type of desired tissue from a mixture of ‘pluripotent’ stem cells, which generate various types of tissue. An ideal transplant would then consist of only tissue-specific stem cells that retain a robust regenerative potential. Pluripotent cells, on the other hand, pose the risk, when transplanted, of generating normal tissue in the wrong location, abnormal tissue, or cancer. Thus, we have concentrated our efforts to devise strategies to either make pluripotent cells develop into desired tissue-specific stem cells or to separate these desired cells from a mixture of many types of cells.
  • Our approach to separating tissue-specific stem cells from mixed cultures is based on the theory that every type of cell has a very specific set of molecules on its surface that can act as a signature. Once this signature is known, antibodies (molecules that specifically bind to these surface markers) can be used to tag all the cells of a desired type and remove them from a mixed population. To improve stem cell therapy, our aim is to identify the signature markers on: (1) the stem cells that are pluripotent or especially likely to generate tumors; and (2) the tissue-specific stem cells. By then developing antibodies to the pluripotent or tumor-causing cells, we can exclude them from a group of cells to be transplanted. By developing antibodies to the tissue-specific stem cells, we can remove them from a mixture to select them for transplantation. For the second approach, we are particularly interested in targeting stem cells that develop into heart (cardiac) tissue and cells that develop into mature blood cells. As we develop ways to isolate the desired cells, we test them by transplanting them into animals and observing how they grow.
  • Thus, the first goal of our program is to develop tools to isolate pluripotent stem cells, especially those that can generate tumors in transplant recipients. To this end, we tested an antibody aimed at a pluripotent cell marker (stage-specific embryonic antigen-5 [SSEA-5]) that we previously identified. We transplanted into animals a population of stem cells that either had the SSEA-5-expressing cells removed or did not have them removed. The animals that received the transplants lacking the SSEA-5-expressing cells developed smaller and fewer teratomas (tumors consisting of an abnormal mixture of many tissues). Approaching the problem from another angle, we analyzed teratomas in animals that had received stem cell transplants. We found SSEA-5 on a small group of cells we believe to be responsible for generating the entire tumor.
  • The second goal of the program is to develop methods to selectively culture cardiac stem cells or isolate them from mixed cultures. Thus, in the last year we tested procedures for culturing pluripotent stem cells under conditions that cause them to develop into cardiac stem cells. We also tested a combination of four markers that we hypothesized would tag cardiac stem cells for separation. When these cells were grown under the proper conditions, they began to ‘beat’ and had electrical activity similar to that seen in normal heart cells. When we transplanted the cells with the four markers into mice with normal or damaged hearts, they seemed to develop into mature heart cells. However, these (human) cells did not integrate with the native (mouse) heart cells, perhaps because of the species difference. So we varied the approach and transplanted the human heart stem cells into human heart tissue that had been previously implanted in mice. In this case, we found some evidence that the transplanted cells differentiated into mature heart cells and integrated with the surrounding human cells.
  • The third goal of our project is to culture stem cells that give rise only to blood cells and test them for transplantation. In the past year, we developed a new procedure for treating cultures of pluripotent stem cells so that they differentiate into specific stem cells that generate blood cells and blood vessels. We are now working to refine our understanding and methods so that we end up with a culture of differentiated stem cells that generates only blood cells and not vessels.
  • In summary, we have discovered markers and tested combinations of antibodies for these markers that may select unwanted cells for removal or wanted cells for inclusion in stem cell transplants. We have also begun to develop techniques for taking a group of stem cells that can generate many tissue types, and growing them under conditions that cause them to develop into tissue-specific stem cells that can be used safely for transplantation.
  • Our program is focused on improving methods to purify blood-forming and heart-forming stem cells so that they can be used safely and effectively for therapy. Current methods to identify and isolate blood-forming stem cells from bone marrow and blood are efficient. In addition, we found that if blood-forming stem cells are transplanted, they create in the recipient an immune system that will tolerate (i.e., not reject) organs, tissues, or other types of tissue stem cells (e.g. skin, brain, or heart) from the same donor. Many living or recently deceased donors often cannot contribute these stem cells, so we need, in the future, a single biological source of each of the different types of stem cells (e.g., blood and heart) to change the entire field of regenerative medicine. The ultimate reason to fund embryonic stem cell and other pluripotent stem cell research is to create safe banks of predefined pluripotent cells. Protocols to differentiate these cells to the appropriate blood-forming stem cells could then be used to induce tolerance of other tissue stem cells from the same embryonic stem cell line. However, existing protocols to differentiation stem cells often lead to pluripotent cells (cells that generate multiple types of tissue), which pose a risk of generating normal tissue in the wrong location, abnormal tissue, or cancers called teratomas. To address these problems, we have concentrated our efforts to devise strategies to (a) make pluripotent cells develop into desired tissue-specific stem cells, and (b) to separate these desired cells from all other cells, including teratoma-causing cells. In the first funding period of this grant, we succeeded in raising antibodies that identify and eliminate teratoma-causing cells.
  • In the past year, we identified surface markers of cells that can only give rise to heart tissue. First we studied the genes that were activated in these cells, further confirming that they would likely give rise to heart tissue. Using antibodies against these surface markers, we purified heart stem cells to a higher concentration than has been achieved by other purification methods. We showed that these heart stem cells can be transplanted such that they integrate into the human heart, but not mouse heart, and participate in strong and correctly timed beating.
  • In the embryo, a group of early stem cells in the developing heart give rise to (a) heart cells; (b) cells lining the inner walls of blood vessels; and (c) muscle cells surrounding blood vessels. We identified cell surface markers that could be used to separate each of these subsets from each other and from their common stem cell parents. Finally, we determined that a specific chemical in the body, fibroblast growth factor, increased the growth of a group of pluripotent stem cells that give rise to more specific stem cells that produce either blood cells or the lining of blood vessels. This chemical also prevented blood-forming stem cells from developing into specific blood cells.
  • In the very early embryo, pluripotent cells separate into three distinct categories called ‘germ layers’: the endoderm, mesoderm, and ectoderm. Each of these germ layers later gives rise to certain organs. Our studies of the precursors of mesoderm (the layer that generates the heart, blood vessels, blood, etc.) led us by exclusion to develop techniques to direct ES cell differentiation towards endoderm (the layer that gives rise to liver, pancreas, intestinal lining, etc.). A graduate student before performed most of this work before he joined in our effort to find ways to make functional blood forming stem cells from ES cells. He had identified a group of proteins that we could use to sequentially direct embryonic stem cells to develop almost exclusively into endoderm, then subsets of digestive tract cells, and finally liver stem cells. These liver stem cells derived from embryonic stem cells integrated into mouse livers and showed signs of normal liver tissue function (e.g., secretion of albumin, a major protein in the blood). Using the guidelines of the protocols that generated these liver stem cells, we have now turned our attention back to our goal of generating from mesoderm the predecessors of blood-forming stem cells, and, ultimately, blood-forming stem cells.
  • In summary, we have continued to discover signals that cause pluripotent stem cells (which can generate many types of tissue) to become tissue-specific stem cells that exclusively develop into only heart, blood cells, blood vessel lining cells, cells that line certain sections of the digestive tract, or liver cells. This work has also involved determining the distinguishing molecules on the surface of various cells that allow them to be isolated and nearly purified. These results bring us closer to being able to purify a desired type of stem cell to be transplanted safely to generate only a single type of tissue.
  • The main focus of our program is to improve methods to generate pure populations of tissue-specific stem cells that form only heart tissue or blood. Such tissue-specific stem cells are necessary for developing safe and effective therapies. If injected into patients with heart damage, heart-forming stem cells might be used to regenerate healthy heart tissue. Blood-forming stem cells are capable of regenerating the blood-forming system after cancer therapy and replacing a defective blood forming-system. We showed that blood-forming stem cells from a given donor induce in the recipient permanent transplant tolerance of all organs, tissues, or other tissue stem cells from the same donor. Therefore, having a single biological source of each of the different types of stem cells (e.g., blood and heart) would revolutionize regenerative medicine.
  • Our projects involve generating tissue-specific stem cells from pluripotent stem cells (PSCs), the latter of which are stem cells that can form all tissues of the body. PSCs (which include embryonic stem cells and induced pluripotent stem cells) can turn into all types of more specialized cells in a process known as “differentiation.” Because PSCs can be grown to very large numbers, differentiating PSCs into tissue-specific stem cells could lead to banks of defined tissue stem cells for transplantation into patients—the ultimate reason to conduct PSC research.
  • However, current methods to differentiate PSCs often generate mixtures of various cell types that are unsafe for injection into patients. Therefore, generating a pure population of a desired cell type from PSC is pivotal for regenerative medicine—purity is a key concern for cell therapy as it is with medications.
  • We have invented technologies to purify desired types of cells from complex cell populations, allowing us to precisely isolate a pure population of tissue-specific stem cells from differentiating PSCs for cell therapy. For instance, in our work on heart-forming cells, we developed labels for cells that progressively give rise to heart cells. We used these labeled cells to clarify the natural, stepwise, differentiation process that leads from PSCs to heart-forming stem cells, and finally to different cells within the heart. Exploiting these technologies to isolate desired cell types, we have completed the first step of turning human PSCs into heart-forming stem cells. In the laboratory, when we transplanted these heart-forming stem cells into a human heart, they integrated with the surrounding tissue and participated in correctly timed beating. In the future we hope to deliver heart-forming stem cells into the damaged heart to regenerate healthy tissue.
  • We have also attempted to turn PSCs into blood-forming stem cells by understanding the complex process of blood formation in the early embryo. As mentioned above, if blood-forming stem cells are transplanted into patients, they create in the recipient an immune system that will tolerate (i.e., not reject) other tissues and types of tissue stem cells (e.g., for skin or heart) from the same donor. Thus, turning PSCs into blood-forming stem cells will provide the basis for all regenerative medicine, whereby the blood-forming stem cells and the needed other tissue stem cells can be generated from the same pluripotent cell line and be transplanted together.
  • In parallel studies to those above, we have turned PSCs into liver-forming stem cells. In the embryo, the liver emerges from a cell type known as endoderm, whereas the blood and heart emerge from a different cell type known as mesoderm. We learned that PSCs could only be steered to form endoderm (and subsequently, liver) by diverting them away from the path that leads to mesoderm. Through this approach, we could turn human PSCs into endoderm cells (at >99% purity) and then into liver-forming stem cells that, when injected into the mouse liver, gave rise to human liver cells. This could be of therapeutic importance for human patients with liver damage.
  • Finally, we have developed methods to deplete PSCs from mixtures of cells differentiated from PSCs, because residual PSCs in these mixtures can form tumors (known as teratomas). These methods should increase the safety of PSC-derived tissue stem cell therapy.
  • In summary, we have developed methods to turn PSCs to tissue-specific stem cells that exclusively develop into only heart, blood cells, or liver cells. This work has involved determining the distinguishing molecules on the surface of various cells that allow them to be isolated and nearly purified. These results bring us closer to being able to purify a desired type of stem cell to be transplanted safely to generate only a single type of tissue.
Funding Type: 
Tools and Technologies III
Grant Number: 
RT3-07763
ICOC Funds Committed: 
$1 382 400
Disease Focus: 
Blood Disorders
Collaborative Funder: 
Australia
Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
Public Abstract: 
Our goal is to develop tools that address major bottlenecks that have prevented the generation of blood forming stem cells in culture for therapeutic use. To help overcome these bottlenecks, we will generate a suite of human embryonic stem cell reporter lines that can be used to monitor key milestones in blood stem cell development. These lines will serve as tools to identify factor combinations to improve the in vitro differentiation of hESCs to functional blood stem cells. Once individual lines have been validated, lines that contain multiple fluorescent reporters will be generated, and a multi factor screen will be performed to optimize conditions that induce these blood stem cell regulators. To track the location and quantity of transplanted cells in recipient small animal model, we will generate hESC lines with in vivo reporter system that combines bioluminescent or PET imaging, and serum-based assay. Our in vivo tracking tools will be broadly relevant and not restricted to studying the in vivo biology of blood forming cells. These tools will help translate the promise of stem cells to cell based therapies to treat human disease.
Statement of Benefit to California: 
This project will help improve California economy as many of the vendors used for reagents and supplies are located in California. This project will also help create and maintain jobs for skilled personnel and helps train post-doctoral fellows who will become the next generation of stem cell scientists. The long-term goal of this project is to improve in vitro differentiation protocols to create transplantable blood forming stem cells for therapeutic use. If we, or others who will use our reporter lines generated in this study, achieve this goal, there will be new, theoretically unlimited sources of HLA-matched or patient specific blood stem cells that can be used for treating many serious blood diseases, including leukemias and inherited immunodeficiencies or anemias. Availability of patient specific blood stem cells for transplantation would be a major benefit in California, as there is currently limited availability of suitable bone marrow donors for individuals from mixed ethnic backgrounds.
Funding Type: 
Basic Biology V
Grant Number: 
RB5-07089
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$614 400
Disease Focus: 
Blood Disorders
oldStatus: 
Active
Public Abstract: 
Blood stem cells living in the bone marrow of adult humans give rise to all of the cells in our blood, including the red blood cells that carry oxygen to supply our body, and the white blood cells such as T and B lymphocytes that fight infections and keep us healthy. Among the T lymphocytes there is a small population called invariant natural killer T (iNKT) cells. Despite their low frequency in humans (~0.001-1% in blood), iNKT cells have the remarkable capacity to mount immediate and potent responses when stimulated, and have been suggested to play important roles in regulating multiple human diseases including infections, allergies, cancer, and autoimmunity (such as Type I diabetes and multiple sclerosis). However, successful clinical interventions with iNKT cells have been greatly hindered by our limited knowledge on how these cells are produced by blood stem cells, largely due to the lack of tools to track these cells in humans. We therefore propose a novel model system to overcome this research bottleneck by transplanting human blood stem cells into a mouse and genetically programming these cells to develop into iNKT cells. This “humanized” mouse model will allow us to directly track the differentiation of human blood stem cells into iNKT cells in a living animal. From this study, we will address some critical unanswered questions for iNKT cell development, and shed light on developing stem-cell based iNKT cell therapies.
Statement of Benefit to California: 
Allergies, cancer and autoimmunity are leading health hazards in California. These diseases affect millions of Californians, impairing their life quality and creating huge economic burdens for the State of California. This proposal intends to study invariant natural killer (iNKT) T cells, a special population of T lymphocytes that have been suggested to play important roles in regulating these diseases. To date, clinical applications of iNKT cells have been greatly limited by their low frequency in humans and their high variability between individuals (~0.001-1% in blood). Thus, an improved understanding of how these cells are naturally generated is important for their use clinically. Like all other cells in blood, iNKT cells are descendants of the blood stem cells that live in the bone marrow of adult humans. Our goal is to study how human blood stem cells give rise to iNKT cells. If successful, our results can be exploited to develop stem cell-based iNKT cell therapies to treat allergies, cancer and autoimmunity, and therefore may benefit the millions of Californians currently suffering from these diseases. In addition, the knowledge and reagents generated from this proposed study will be shared freely with non-profit and academic organizations in California, and any new intellectual property derived from this study will be developed under the guidance of CIRM to benefit the State of California.
Progress Report: 
  • Despite their small numbers (~0.001-1% in blood), invariant natural killer T (iNKT) cells in humans have been suggested to play important roles regulating multiple diseases including infections, allergies, cancer and autoimmunity. Like all other immune cells, iNKT cells are derived from the blood stem cells living in the bone marrow of adult humans. Successful clinical interventions with iNKT cells have been greatly hindered by our limited knowledge on how these cells are produced by blood stem cells, largely due to the lack of tools and track these cells in humans. Our project proposes to overcome this research bottleneck by transplanting human blood stem cells into a mouse and genetically engineer these cells to develop into human iNKT cells. This “humanized” mouse model will allow us to directly track the differentiation of human blood stem cells into iNKT cells in a living animal. In this reporting period, we have demonstrated the feasibility of this model system, and have successfully generated stem cell-engineered human iNKT cells. In the coming year, we plan to use this established model system to address some critical unanswered questions for iNKT cell development, and explore the therapeutic potential of stem-cell based iNKT cell therapies.
Funding Type: 
Research Leadership 12
Grant Number: 
LA1_C12-06917
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$6 152 065
Disease Focus: 
Blood Disorders
Stem Cell Use: 
iPS Cell
oldStatus: 
Closed
Public Abstract: 
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.
Statement of Benefit to California: 
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.
Funding Type: 
New Faculty Physician Scientist
Grant Number: 
RN3-06532
Investigator: 
ICOC Funds Committed: 
$2 836 742
Disease Focus: 
Blood Disorders
Pediatrics
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
Many fetuses with congenital blood stem cell disorders such as sickle cell disease or thalassemia are prenatally diagnosed early enough in pregnancy to be treated with stem cell transplantation. The main benefit to treating these diseases before birth is that the immature fetal immune system may accept transplanted cells without needing to use immunosuppressant drugs to prevent rejection. Moreover, transplanting stem cells into the fetus—in which many stem cell types are actively multiplying and migrating—can promote similar growth and differentiation of the transplanted cells. Although this strategy works well in animal models, when applied clinically, the number of surviving cells in the blood (“engraftment”) has been too low to achieve a reliable cure. Our lab studies ways to improve engraftment, with the long-term goal of applying these strategies to treat fetuses with congenital blood disorders. In this application, we will use novel embryonic stem cells that may be better suited to differentiate into blood cells in the fetal environment. We will also test various approaches to improve the survival advantage of these stem cells in fetal organs that make blood cells. Finally, we will study the fetal immune system to determine how fetuses become tolerant to the transplanted cells. The experiments in this proposal will give us important information to design clinical trials to treat fetuses with common, currently incurable stem cell disorders.
Statement of Benefit to California: 
The long-term goal of our project is to develop safe and effective ways to perform prenatal stem cell transplantation to treat fetuses with congenital blood disorders, such as thalassemia and hemoglobin disorders. These diseases affect many California citizens. For example, hemoglobin disorders are so common that they are routinely screened for at birth (and prenatal screening is performed if there is a family history). Thalassemias are found more commonly in persons of Mediterranean or Asian descent and are therefore prevalent in our state’s population. Prenatal screening is routinely offered, especially to patients with a family history or those with an ethnic predisposition. Fetal stem cell transplantation would also benefit children with sickle cell disease, 2000 of which are born each year in the United States, and inborn errors of metabolism, which occur in 1 in 4000 births. Thus, once we develop reliable techniques to treat these disorders before birth, there will be an enormous potential to make a difference. Fetal surgery was pioneered in California and is performed only in select centers across the country. Therefore, once we have developed safe and effective therapies for fetuses with stem cell disorders, we also expect increased referrals of such patients to California. The convergence of our expertise in fetal therapies with those in stem cell biology carries great promise for finally realizing the promise of fetal stem cell transplantation.
Progress Report: 
  • Our group works on developing methods for successful transplantation of blood stem cells to treat fetuses with genetic disorders such as sickle cell disease or thalassemia. In this grant, we are using novel stem cells that will differentiate into blood-forming cells and other techniques to improve the “engraftment” of these cells. This year, we focused on using a new technique that creates “space” in the bone marrow of the recipient using an antibody (ACK2) to deplete the host’s blood stem cells. In a mouse model, we showed that this antibody is very effective is improving the engraftment of transplanted blood stem cells. In fact, the treatment is more effective in the fetal environment than the adult. These findings were recently published and we are planning to use this strategy in the monkey model as a step toward clinical applications. We are also working on transplanting human blood stem cells into immunodeficient mouse fetuses to understand whether different sources of stem cells vary in their ability to make blood cells in this setting.
Funding Type: 
Transplantation Immunology
Grant Number: 
RM1-01718
Investigator: 
ICOC Funds Committed: 
$1 324 229
Disease Focus: 
Pediatrics
Immune Disease
Blood Disorders
Stem Cell Use: 
Other
oldStatus: 
Active
Public Abstract: 
The immune system is the body’s defense system against disease and can recognize foreign cells. Because of this, stem cells and organs that are transplanted from one person to another are usually “rejected” by the immune system, forcing doctors to use powerful immune suppressive drugs with severe side effects. This natural defense system will therefore limit our ability to use stem cell therapies until we develop better solutions to prevent rejection (“induce tolerance”). We are developing a unique solution to this problem: if we transplant cells in utero, before the immune system is fully developed, we can educate the fetus to tolerate the foreign cells and avoid rejection without using any drugs. This strategy could be useful for many inherited stem cell disorders such as sickle cell disease, thalassemias, and muscular dystrophy. In addition, if tolerance to a particular donor is established, it may be used to transplant an organ (eg. kidney) from the same donor for other congenital anomalies. Many of these diseases can be diagnosed early in pregnancy and the surgical expertise for performing the transplants safely already exists. Although this strategy has been successful in animal models, cells transplanted in utero have mostly been rejected and we have been doing research to improve these results. Our lab has recently made the important discovery that the mother’s immune system is also responsible for rejection: we believe that cells from the mother help the immature fetal immune system develop faster and facilitate rejection of the transplanted cells. In this proposal, we will study this idea in both an animal model and in patients who have fetal surgery for other diseases. We will examine whether surgery leads to changes in the mother and fetus which prompt rejection of the transplanted cells. The strategy of treating stem cell disorders in utero to avoid rejection has a high likelihood of success and our team is uniquely qualified to perform a clinical trial of in utero stem cell transplantation once we have evidence of safety and efficacy in animal models. The experiments in this proposal will give us important information to design innovative treatments for common, currently incurable stem cell disorders.
Statement of Benefit to California: 
The long term goal of our team is to develop strategies for safe and effective stem cell transplants to cure fetuses with congenital stem cell disorders. Many common diseases can be diagnosed early in pregnancy and may potentially be treated with in utero stem cell transplantation. For example, blood stem cells may be used to treat sickle cell disease and thalassemias. Muscle stem cells may be used to treat muscular dystrophies and liver stem cells may be used to treat metabolic disorders. Furthermore, transplantation of blood stem cells may be used to develop tolerance to a particular donor so that organs can be transplanted without immunosupression. Recent progress in our understanding of immune interactions between the mother and fetus has brought us closer to realizing this goal. Congenital stem cell disorders are common and affect many patients in California. For example, hemoglobin disorders are so common that they are routinely screened in all babies (and prenatal diagnosis can be done if there is a family history): each year, 2000 children are born with sickle cell disease in the United States, 150 children in California alone (www.scdfc.org). Thalassemias are found more commonly in persons of Mediterranean or Asian descent and are therefore prevalent in our state’s population. Muscular dystrophy affects 1/3500 births and currently has no cure while inborn errors of metabolism affect 1/4000. Given that more than 500,000 children are born each year in California, the potential to make a difference is enormous. Furthermore, our studies will improve our knowledge about the uniquely tolerant state of the fetus and may allow us to then design treatments to improve tolerance in adult patients. in utero surgery was born in California and is performed in only select centers in the country. Therefore, once we have developed safe and effective therapies for stem cell disorders, we also expect increased referrals of such patients to California. The convergence of our expertise in fetal therapies with those in stem cell biology carries great promise for finally realizing the promise of in utero stem cell transplantation.
Progress Report: 
  • We are working on developing better treatments for patients with genetic stem cell disorders. Our strategy is to treat fetuses before birth with stem cell transplantation in order to induce tolerance to the foreign transplanted cells and avoid immunosuppression. We have noted that the mother’s immune system is involved in rejecting the cells that are transplanted into the fetus and are now studying how the fetal immune system responds to the transplant. This year, we learned that the fetal immune system becomes aware of the transplanted cells as early as 2 weeks after the transplant. However, T cells that would react to the transplant are also deleted, which is one way that the fetus learns to tolerate the foreign cells. We are also analyzing immune development in human patients who undergo fetal surgery. In our analysis of human patients, we learned that open fetal surgery increases the amount of maternal cells that have trafficked into the fetus. We are now studying whether the fetus becomes sensitized or tolerant to these maternal cells after surgery.
  • We are working on developing better treatments for patients with genetic stem cell disorders. Our strategy is to treat fetuses before birth with stem cell transplantation in order to induce tolerance to the foreign transplanted cells and avoid immunosuppression. We have noted that the mother’s immune system is involved in rejecting the cells that are transplanted into the fetus. We are now studying how the fetal immune system responds to the transplant. This year, we learned that, although the fetal immune system becomes tolerant to the transplanted cells by deleting T cells, it does not become tolerant by making regulatory T cells, which would be a more robust mechanism of tolerance. Therefore, the strategy of adding in more regulatory T cells may boost tolerance. We are also analyzing immune development in human patients who undergo fetal surgery. We have refined our assays to include the most relevant pathway by which maternal T cells recognize the foreign fetus and have found that, in addition to maternal T cells recognizing the fetus, fetal T cells are also capable of recognizing the mother. We are now understanding whether this recognition is enhanced after fetal surgery, which would indicate sensitization and possible rejection.
  • Our lab studies in utero hematopoietic stem cell transplantation as a way novel strategy to treat fetuses with congenital stem cell disorders. This method can potentially allow us to transplant genetically foreign stem cells without rejection by the immune system. In our previous experiments, we have determined that the mother's immune system can be a barrier to success but the fetal immune system does not reject the transplanted cells. In these experiments, we first used a mouse model and performed a detailed analysis of the fetal host immune response to transplantation to understand why rejection does not occur. We also analyzed human maternal and cord blood samples to understand human fetal immune maturation, to determine whether clinical applications will involve any immune response from the fetus or the mother. Our results are an exciting preclinical platform for considering in utero transplantation for fetuses with disorders such as hemoglobinopathies.
  • We are working on developing better treatments for patients with genetic stem cell disorders. Our strategy is to treat fetuses before birth with stem cell transplantation in order to induce tolerance to the foreign transplanted cells and avoid immunosuppression. We have noted that the mother’s immune system is involved in rejecting the cells that are transplanted into the fetus and are now studying how the fetal immune system responds to the transplant. We have also examined whether the fetus becomes sensitized or tolerant to these maternal cells after surgery and have made the surprising discovery that the fetal immune system also becomes activated after pregnancy complications.
Funding Type: 
Tools and Technologies III
Grant Number: 
RT3-07692
Investigator: 
ICOC Funds Committed: 
$1 416 600
Disease Focus: 
Blood Disorders
Stem Cell Use: 
Adult Stem Cell
Public Abstract: 
Tens of thousands of patients need bone marrow transplants (BMT) every year, some for bone marrow (BM) cancers and some for inherited diseases such as sickle cell anemia and thalassemia, but many lack a BM donor. African Americans, Asian Americans, and people of Hispanic descent are more likely than others to lack a stem cell donor. BMTs provide hematopoietic (blood) stem and progenitor cells (HS/PCs) that replace the patient’s diseased BM with healthy BM. The new BM provides all the circulating blood cells throughout life. Many BMTs use HS/PCs that do not come from the BM. One such ‘other’ source is umbilical cord blood (UCB). UCB HS/PCs have many advantages over other HS/PC sources (i.e., BM or peripheral blood). For example, we can easily obtain UCB HS/PCs without any risk to the donor, and we can keep the cells stored in freezers to be available when a patient needs them. However, most UCB samples contain too few HS/PCs to be used to treat people. Expanding the number of HS/PCs in UCB samples will increase the number of clinically usable UCB samples, offering new hope for thousands of patients who currently lack a donor. We previously screened >120,000 compounds for their ability to expand UCB HS/PCS, and identified a short list of lead candidates. This grant will fund the next step in our effort to develop a novel, clinically-useful UCB HS/PC expansion protocol. Successful completion of this proposal will result in life-saving treatment for thousands of patients.
Statement of Benefit to California: 
Our proposal seeks to establish a novel method to expand umbilical cord blood hematopoietic stem/progenitor cells (HS/PCs) to make bone marrow transplants (BMTs) available to thousands of patients who currently lack a stem cell donor. The benefits to California are wide-ranging: • Grow California’s skilled workforce and create jobs: This project will train scientists in stem cell research and technology, and our success will attract more talent from outside California. • Increase innovation: This proposal is highly translational, with a goal to move rapidly from bench to bedside. However, our research will also provide basic insights into stem cell biology that can be applied by other scientists to help patients more broadly. • Enhancing the medical treatment of California residents: Compounds that expand UBC HS/PCs have the potential to improve clinical benefit and reduce health care costs by increasing the success rate of stem-cell transplants. Given California’s diverse ethnic population, we have many patients who need a BMT yet lack a donor, so our residents will directly benefit from our success. • Attracting venture capital and commercialization: We aim to develop technology that will be highly attractive to the biotechnology industry. We have identified GE as a partner to commercialize our reagents and processes. Furthermore, commercially viable compounds will attract venture capital to fund cell therapies and create new biotech jobs for the California economy.

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