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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.
The overall goal of this proposal is to develop in utero strategies for safe and effective stem cell transplantation to treat congenital stem cell disorders. In utero transplantation is a promising strategy because the immature immune system is likely to be more accepting of allogeneic cell transplants. While this strategy has been successful in animal models, it has been mostly unsuccessful in human patients. The applicant has recently discovered that the rejection of transplanted cells in humans is mediated by the mother’s immune system, but rejection also persists after maternal cells are no longer present These discoveries are the basis for this proposal’s two specific aims: (1) to examine immune responses to in utero hematopoietic stem cell transplantation (IUHSCTx) and test interventions to improve tolerance and engraftment in a preclinical model; and (2) to examine immune responses by utilizing umbilical cord and maternal blood samples from patients undergoing medically necessary, minimally invasive interventions. Reviewers found this proposal to be innovative and appreciated its development of novel models for in utero transplantation to enhance tolerance of allogeneic stem cell grafts. Some reviewers felt that it could have a significant impact on the treatment of patients with inherited diseases that are amenable to hematopoietic stem cell transplantation and, eventually, other inherited diseases as well. Other reviewers were uncertain about the potential for clinical translation however, given the differences between the development of mouse and human immune systems, as well as the safety concerns associated with in utero interventions. The reviewers described this proposal as dense and difficult to read, but also recognized its strengths. Reviewers found the rationale to be sound and based upon successful protocols, publications, and preliminary data. Reviewers appreciated the quality of the preliminary data presented, which suggest a high level of expertise necessary to perform the proposed experiments. One reviewer noted that the applicant did not address the feasible alternative hypothesis that maternal T cells exist below the level of detection but still mediate rejection of the graft. They raised minor concerns with the research plan, but in general found it to be feasible. With regard to Aim 1, reviewers made several suggestions. One reviewer noted that the overall approach relies on the transient influx of maternal T cells, which occurs in approximately two-thirds of mice. This reviewer suggested that a more direct, and potentially more powerful, strategy would include the direct injection of maternal cells, either whole populations or unique defined subsets. Regarding Subaim 1b, a reviewer noted that mixed leukocyte reactions to allogeneic antigens from third parties should be performed in parallel to the proposed assays. This reviewer found Subaim 1c to be unfocused, and was unclear how a blocking strategy would be chosen or whether the regulatory T cell approach is feasible. Reviewers had mixed opinions about the rationale for Aim 2. One reviewer did not find these studies relevant to those proposed in Aim 1 and was not convinced they would serve as an accurate model for IUHSCTx. Other reviewers disagreed, noting that Aim 2 is descriptive but could provide valuable support for the applicant’s hypothesis. Reviewers described the principal investigator (PI) as an outstanding junior investigator with a solid publication record. However, they did note that the PI has few recent publications and none as a senior author. They also regarded the 10% effort from this PI as insufficient for such a junior investigator on a project of this scope. However, one reviewer pointed out that the PI’s percent effort may be limited by a NIH K08 award. Reviewers appreciated that the PI has assembled an outstanding collaborative team, including a Co-Investigator with expertise in transplant immunology and several talented senior investigators. They felt that the contributions of these team members improved the project’s likelihood of success. Overall, reviewers raised some concerns about the research plan and the potential for clinical translation but agreed that this innovative proposal addresses an important question and is likely to produce valuable data. PROGRAMMATIC REVIEW A motion was made to move this application into Tier 1, Recommended for Funding. Reviewers noted that this proposal is unique among Tier 1 applications in its focus on in utero transplantation and the PI is a talented junior investigator who is likely to succeed. The motion carried.
- Alan W. Flake
- Bruce Blazar