Preeclampsia (PE) is a pregnancy complication, characterized by high blood pressure and abnormal kidney function, which affects 5-8% of all pregnancies. It is responsible for a significant proportion of maternal deaths and growth-restricted babies; it is also a major reason why obstetricians induce delivery prematurely, resulting in additional neonatal complications, often requiring extended stays in neonatal intensive care units. PE is a disease of the placenta, an organ which supports the fetus during intrauterine life. In PE, a subpopulation of placental cells called “extravillous trophoblast” (EVT) fail to properly develop: in their absence, the placenta does not receive enough blood supply and therefore cannot support fetal growth. PE is difficult to study: it spontaneously develops only in higher primates, and available human trophoblast cell lines are of limited use. Using normal human ES-derived trophoblast precursors, we propose to screen for drugs which can increase EVT differentiation. We will also apply stem cell-based technology to cells from placentas of PE patients, in order to develop “disease-in-a-dish” models for PE. We will then test the ability of the drugs, identified above, to restore EVT differentiation in these PE models. If successful, this application will 1) establish the first true cell culture model for preeclampsia, and 2) identify drugs for its treatment.
On an average day in California, 149 babies are born prematurely. Many of these babies will require weeks of care in a neonatal intensive care unit, at an average per patient cost of $25,000 (compared to the $1,500 per patient cost of a baby born at term). The #1 reason obstetricians induce preterm delivery is a disease called preeclampsia, where mom develops high blood pressure and other serious complications during pregnancy. Preeclampsia is also responsible for ~20% of maternal deaths in pregnancy. Preeclampsia is not well-understood, but is known to be a disease of the placenta, an organ which forms the interface between mother and baby. Our lab is one of few in the world that focuses on stem cells which give rise, not to the baby, but to the placenta: these are called trophoblast stem cells. We have recently developed a human trophoblast stem cell model, which can be used to study events during placental development, never before possible in the human. This proposal, if funded, would extend these findings to develop ground-breaking models for studying preeclampsia and identifying drugs for its treatment. If successful, this research would benefit the state of California by developing therapies which would prevent preeclampsia, and therefore a significant proportion of preterm births and its complications. This would lead, not only to improved health of moms and babies, but also save the state millions in cost of prolonged stays in neonatal intensive care units.
The applicant proposes to employ human induced pluripotent stem cell (hiPSC) technology to discover novel therapeutic agents for the treatment of preeclampsia, a pregnancy disorder characterized by hypertension in the mother and preterm births. The proposed study is based on evidence that preeclampsia involves abnormal differentiation or function of a specific cell type in the placenta, called extravillous trophoblast (EVT), which plays a role in establishing the blood vessels of the fetal-placental unit. The applicant has developed a method to derive multipotent placental progenitor cells from human embryonic stem cells (hESC), and proposes in Aim 1 to screen chemical libraries for small molecules that promote the differentiation of such progenitors to EVT. Based on evidence that genetic predisposition contributes to this disorder, the applicant will investigate in Aim 2 whether hiPSC derived from patients with severe, early onset preeclampsia show a defect in EVT differentiation or function that can be rescued using select small molecules identified in Aim 1.
- The project addresses an unmet medical need, given the major problem of preterm labor.
- The development of a disease-specific cellular model of preeclampsia would be highly significant, as this is a primate-specific disorder for which animal models do not exist.
- The rationale for the proposed research is overall logical and compelling, but does depend on the validity of the underlying premise that preeclampsia is caused by abnormal differentiation or function of EVT. Reviewers cautioned that interactions amongst different cell types might need to be considered for developing a disease in a dish model.
-The screening of small molecule libraries using hiPSC-based models for reversal of cellular defects is a logical first step in developing pharmacologic therapies for preeclampsia.
- This application is directed toward an important but relatively neglected area of stem cell biology, the placenta, and brings a novel approach to this field.
- Aim 1 is supported by compelling preliminary data, and reviewers expressed confidence that the proposed screens should identify candidate molecules for enhancement of EVT differentiation and/or function.
- The feasibility of Aim 2 depends on whether the proposed disease in a dish model will exhibit a defect relevant to preeclampsia. Preliminary evidence from a disorder with a different placental defect is somewhat supportive of this notion but overall this represents a risk of the proposal.
- The team has the necessary equipment and material resources to accomplish the work described. The applicant has appropriate access to patient material and the patient selection criteria for hiPSC derivation are well founded.
- The time line and budget are appropriate.
- The Principal Investigator (PI) is very well qualified to perform the proposed studies. The PI is well trained, has an appropriate background and has a good track record of independent funding and publishing. The applicant’s clinical work is consistent with his/her research interests.
- The applicant is ideally positioned to become a leader in the area of placental stem cell biology, and has developed the tools within his/her laboratory to generate novel data on placental stem cells.
- The applicant presents an effective plan for developing a successful career in translational stem cell research and is supported by an outstanding group of mentors that appear committed to his/her career success.
- The collaborations to support hiPSC generation and small molecule screening are essential and appear to be in place and active.
- Because the applicant’s research focus lies in a relatively underfunded and underappreciated research area, the CIRM award is critical to his/her ongoing career development.
- The institution appears committed to the applicant’s translational research career.
- There appears to be excellent collaborative potential within the applicant’s environment.
- The institution has an outstanding track record and firm commitment to translational studies in stem cell therapy.
- The proposal is highly responsive to the RFA. It utilizes human iPSC and is highly translational with goals of both the development of a disease in a dish model for the study of preeclampsia, and the identification of candidate small molecule therapeutic agents for its treatment.
- The proposed project may be regarded as being too high risk and in part exploratory to receive federal funding; reviewers thus considered it a good fit for this CIRM awards mechanism.