Nonhuman Primate Model for Preclinical Evaluation of Haplotype-Based iPSC Banking for HLA-matched Blood Products

用于 HLA 匹配血液制品基于单倍型 iPSC 库的临床前评估的非人灵长类动物模型

• 批准号: 9276794
• 负责人: Igor I. Slukvin
• 金额: $ 63.11万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276794
• 关键词: Alloimmunization; Animal Model; Animals; Antibody Response; Applications Grants; Autologous; Blood Cells; Bone Marrow Suppression; Bone Marrow Transplantation; CD34 gene; Cell Line; Cell Therapy; Cell Transplants; Cells; Clinic; Clinical Trials; Enrollment; Evaluation; Experimental Models; Foundations; Founder Generation; Future; Genetic Screening; Goals; Haplotypes; Hematological Disease; Hematopoietic; Hematopoietic stem cells; Histocompatibility; Human; Immune; Immunologics; Macaca; Major Histocompatibility Complex; Measures; Modeling; Myelosuppression; PTPRC gene; Population; Pre-Clinical Model; Production; Research; Risk; Safety; Stem cell transplant; Stem cells; Testing; Tissues; Transfusion; Translations; Transplantation; Treatment Efficacy; base; blood group; blood product; cell bank; clinical translation; cost; cytopenia; design; efficacy evaluation; human disease; immunogenicity; in vivo; induced pluripotent stem cell; nonhuman primate; novel; preclinical evaluation; public health relevance; research clinical testing; response; scale up; stem cell therapy

Project Summary/Abstract 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.

项目总结/文摘