Optimizing grafts for in utero transplantation through study of the changing potentials of hematopoietic stem cells in early ontogeny
New Faculty II
This research project is aimed at developing improved methods to blood cell diseases such as thalassemia and sickle cell anemia by stem cell transplantation prior to birth. It is now possible to detect many inherited diseases early in pregnancy. It may also be possible to treat diseases that prevent normal stem cell function by transplantation of healthy stem cells into a fetus with a birth defect. There are potential advantages to such a therapy such as early treatment of disease and a lower risk of rejection because the immune system is not fully developed early in fetal development. This proposal aims to determine the best type of stem cells for fetal transplantation by studying the growth and differentiation properties of blood stem cells at different ages of development to determine if young stem cells are best for prenatal transplantation. This proposal will also test the role of a type of immune cell, natural killer cells, in aiding engraftment of stem cells transplanted into fetuses. These studies will result in a better understanding of the optimal type and mixture of stem cells and blood cells for prenatal transplantation.
Statement of Benefit to California:
This study is aimed at improving the method of prenatal transplantation to treat inherited birth defect that affect the normal function of blood cells. Currently this form of therapy works for some rare forms of immunodeficiency but, if the effectiveness at which healthy stem cells can be introduced to fetuses improves, many more diseases could be treated. Transplanting healthy cells offers treatment or a cure for many blood diseases such as those that affect the function of red blood cells, collectively referred to as hemoglobinopathies. These diseases affect lives of thousands of California denizens. The lack of available or suitable donor tissue prevents therapy in many cases. Prenatal transplantation offers the hope of avoiding the need for tissue matching thus allowing for treatment of the disease before birth, which may lead to a life-long cure of the disease. The successful outcome of this work will offer new hope to many future Californians and their families suffering from inherited blood cell diseases. This will improve lives and save money on long-term health care costs associated with these diseases. Development of the technologies and expertise to bring these novel forms of therapy from the laboratory bench to hospital bedside will also keep California in the forefront of the biotechnology industry, will attract talented scientists and clinicians to California and will create high-paying jobs.
This proposal is focused on in utero transplantation (IUT) for correction of hematopoietic diseases. The scientific rationale is based on the notion that: a) IUT could correct certain pre-natal diagnosed diseases at a very early stage, before significant progression and/or damage occurs, b) IUT may circumvent problems associated with the rejection of allogeneic donor cells because the immune system is not fully developed early in fetal development. The principal investigator (PI) plans to investigate allogeneic hematopoietic stem cells (HSC) from different ages of development for their engraftment potential in transplantation models. The lineage differentiation biases of these different HSC will also be evaluated in vitro and in vivo and finally, human donor natural killer (NK) cells will be assessed for their ability to facilitate engraftment in an in utero xenotransplantation model. This proposal concerns an important and significant problem - the treatment of hematopoietic diseases for which current therapies are ineffective. However, reviewers were unenthusiastic about the application because of serious deficiencies in the feasibility of the research plan. For example, the applicant proposes to study the lineage potential of human HSCs from various developmental ages using in vitro models and xenotransplantation into immuno-deficient mice. Reviewers considered the proposed in vivo studies to assess lineage potential to be very ambitious and should have been supported by preliminary data. They also wondered about the influence of mouse environment on the differentiation potential of human cells. Moreover, the applicant does not discuss how this information will be used to inform future preclinical and clinical studies. Some reviewers also found a disconnection between the different aims of this proposal and some were not convinced that the addition of donor NK cells described by the applicant would provide useful information. Previous attempts to add various lymphocyte components to the HSC to facilitate engraftment in IUT have yielded mixed results with increased engraftment accompanied with enhanced graft versus host (GVHD) disease. The reviewers considered some of the methodologies described in the proposal for assessment of donor cell engraftment in in vivo models to be of insufficient sensitivity and unrealistic. Finally, reviewers pointed out that despite the fact that comparative analysis of different sources of allogeneic HSCs for their engraftment potential may provide important information, from a therapeutically practical point of view, sources of donor cells may be constrained by availability and so clinical practice may be constrained to work with adult cells. The reviewers concurred that the PI is experienced in the field of study. He/She has published many papers related to in utero HSC transplantation in stem cell and hematology journals. The applicant is at a start up phase at his/her institution. The reviewers judged the institutional support to be good including clear financial and intellectual commitment to the applicant’s career development. The mentors include experienced and well-recognized scientists with good mentoring experience although none have direct experience in IUT. Overall, reviewers did not find this application suitable for funding under this RFA.