Recent advances in hematopoietic differentiation from human induced pluripotent stem cells (iPSCs) have brought the clinical translation of iPSC-derived blood products closer to reality and highlight the need for the developing of novel animal models for preclinical evaluation of the efficacy, safety, and immunogenicity of iPSC-derived blood products. Because iPSCs can be derived from the intended recipient, they offer the possibility to generate autologous blood cells in unlimited numbers and avoid HLA alloimmunization. However, the high costs of personalized stem cell therapy and its complexity makes it currently impractical for broad application. Creation of iPSC banks has been proposed as an approach to supply HLA-matched blood cells. Yet, iPSC banking using random donors would remain impractical due to the high variability of HLA. The banking iPSCs from HLA-homozygous donors (haplotype-based banking strategy) has been suggested to be an effective way to provide a scalable off-the-shelf supply of immunologically compatible cells for cellular therapies and maximize the utility of stem cell banking. Thus, developing experimental models for banking HLA homozygous iPSC lines and assessing their immunogenicity, therapeutic efficacy, and safety will be essential to the future design and utility of stem cell banks for manufacturing HLA-compatible blood products. Here, we propose to establish a nonhuman primate model for banking major histocompatibility (MHC) homozygous iPSC lines for transfusion therapies. The proposed model will employ Mauritian cynomolgus macaques, which are descendent from a small founder population and have very limited MHC diversity consisting of only seven common haplotypes (M1-M7). This provides a unique opportunity to rapidly select MHC homozygous and MHC and blood group-identical animals or animals with well-defined MHC mismatches by genetic screening. We will use this model to evaluate the utility and safety of MHC homozygous iPSC-derived CD34+CD45+CD38- multipotent hematopoietic progenitors in the treatment of cytopenia following myeloablative stem cell transplantation and test the hypothesis that transfusion of imHPs derived from MHC-matched homozygous iPSCs reduces HLA alloimmunization.
In aim 1, we will establish a MHC homozygous NHP model for preclinical evaluation of MHC compatible iPSC-derived blood products.
In aim 2, we will evaluate the efficacy and safety of MHC homozygous iPSC-based therapies for acquired bone marrow suppression in MCM model.
In aim 3, we will assess the alloimmune responses toward MHC homozygous imHPs following transfer across MHC barriers. Overall, the proposed research will demonstrate the utility and safety of using MHC homozygous iPSC-derived hematopoietic cells for the treatment of myelosuppression and HLA alloimmunization reduction.

Public Health Relevance

/Public Health Relevance Statement This grant proposal will develop a preclinical model for evaluation of the clinical efficacy, immunogenicity and safety of HLA-matched blood products generated from MHC-homozygous induced pluripotent stem cells. Evaluation of iPSC-derived blood products in a nonhuman primate model would be essential for their translation into the clinic as these studies will provide the scientific rationale to initiate clinical trials and to counterbalance the potential risks to subjects enrolled in clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL132891-02
Application #
9276794
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Yang, Yu-Chung
Project Start
2016-06-01
Project End
2020-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Pathology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715