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.

项目摘要/摘要 造血分化与人类诱导多能干细胞（IPSC）的最新进展具有 使IPSC衍生的血液产品的临床翻译更接近现实，并强调了对 开发新型动物模型，以评估疗效，安全性和免疫原性 IPSC衍生的血产品。因为IPSC可以从预期的收件人中得出 以无限数量产生自体血细胞并避免HLA同种异体免疫的可能性。然而， 个性化干细胞疗法的高成本及其复杂性使其目前不切实际地不切实际 应用。已经提出了IPSC银行的创建作为供应HLA匹配的血细胞的一种方法。 但是，由于HLA的差异很高，使用随机供体的IPSC银行业务将不切实际。这 HLA-Homozygous捐赠者的银行IPSC（基于单倍型的银行业策略）被认为是 为细胞提供可扩展的免疫学兼容细胞的可扩展现成的供应的有效方法 治疗并最大化干细胞库的效用。因此，开发用于银行HLA的实验模型 纯合IPSC线并评估其免疫原性，治疗功效和安全性将是必不可少的 干细胞库的未来设计和实用性用于制造HLA兼容血液产品。在这里，我们 建议建立一个非人类灵长类动物模型，用于银行主要组织相容性（MHC）纯合IPSC 输血疗法的线条。拟议的模型将采用毛里求斯cynomolgus猕猴，这是 来自小型创始人人口的后代，MHC多样性非常有限，只有七个 常见单倍型（M1-M7）。这为快速选择MHC纯合子和MHC提供了独特的机会 以及通过基因筛查具有明确定义的MHC不匹配的血型的动物或动物。我们将 使用此模型评估MHC纯合IPSC衍生的CD34+CD45+CD38-的效用和安全性 多能型造血祖细胞在骨髓性干细胞后的细胞质治疗中 移植和检验以下假设：源自MHC匹配的纯合子的IMHP的输血 IPSC减少了HLA同种异体免疫化。在AIM 1中，我们将建立一个MHC纯合NHP模型 MHC兼容IPSC衍生的血液产品的临床前评估。在AIM 2中，我们将评估功效 MHC纯合子基于IPSC的安全性在MCM模型中获得了获得的骨髓抑制。 在AIM 3中，我们将评估转移后对MHC纯合IMHP的同种异体免疫反应 MHC障碍。总体而言，拟议的研究将证明使用MHC的实用性和安全性 纯合IPSC衍生的造血细胞用于治疗骨髓抑制和HLA 同种免疫减少。