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.
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.
The overall goal of the proposed research program is to address several fundamental and translational hurdles that if overcome, could be broadly enabling for the development of stem cell-based therapies for treating congenital blood disorders such as thalassemia and sickle cell disease. Three aims have been proposed to achieve these ends, each focused on a separate challenge. In the first aim, the applicant will use a prenatal rodent model to explore the engraftment and differentiation potential of hematopoietic stem cells (HSC) derived from a primitive type of human embryonic stem cells (hESC). Next, the applicant will explore and manipulate the host microenvironment to develop strategies for improving HSC engraftment in the prenatal milieu. Finally, the applicant will combine immunomodulation with optimization of cell source and microenvironment to achieve robust engraftment and donor-specific tolerance of human HSC in a relevant preclinical model.
- The proposal addresses several critical barriers to successful clinical application of stem cell derived therapies and if successful, has the potential to significantly advance the field of regenerative medicine.
- The research plan is innovative and based on compelling rationale and supportive preliminary data. Meaningful and realistic considerations of timelines, budget needs, potential pitfalls and alternative solutions have been provided.
- Some reviewers questioned the value of the antibody proposed for host depletion (Aim 2), as there is little information available to support its robustness or reproducibility.
- As the applicant is relatively inexperienced with human embryonic stem cells (hESC), some reviewers questioned the impact of Aim 1 and were uncertain whether the novel lines would offer significant advantages over conventional hESCs. Others, however, believed that the biology explored in Aim 1 is an excellent complement to the more translational goals of Aims 2 and 3, which are well within the applicant’s core competency.
Principal Investigator (PI)
- The PI is a well trained physician with an excellent track record of success and is poised to become a leader in the field. His/her clinical duties are highly relevant to the proposed research.
- The PI has proposed an effective plan for developing a successful career in stem cell translational research and chosen an all-star cast of appropriate mentors with proven track records of mentorship.
- Some reviewers believed that 20% clinical effort might be somewhat excessive for a physician scientist ant this stage of his/her career.
- The institution has made a significant commitment to the PI’s career development, providing generous lab space and appropriate time, personnel, and necessary equipment.
- The institution has an established track record for recruiting faculty and fellows with similar research interests, thus creating a nurturing environment.
- This proposal is highly responsive to the RFA: human stem cells are used, the research is translational in nature, and the proposed research is unlikely to be federally funded.
- Alan W. Flake