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: 9153287
• 负责人: Igor I. Slukvin
• 金额: $ 60.12万
• 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/9153287
• 关键词: Alloimmunization; Animal Model; Animals; Antibody Response; Applications Grants; Autologous; Blood Cells; Blood typing procedure; Bone Marrow Suppression; Bone Marrow Transplantation; CD34 gene; Cell Line; Cell Therapy; Cell Transplants; Cells; Clinic; Clinical; Clinical Trials; Enrollment; Evaluation; Experimental Models; Foundations; Founder Generation; Future; Genetic Screening; Goals; Haplotypes; Hematological Disease; Hematopoietic; Histocompatibility; Histocompatibility Testing; Human; Immune; Macaca; Major Histocompatibility Complex; Measures; Modeling; Myelosuppression; PTPRC gene; Population; Pre-Clinical Model; Production; Research; Risk; Safety; Stem cell transplant; Stem cells; Testing; Transfusion; Translations; Transplantation; Treatment Efficacy; abstracting; base; blood group; blood product; cell bank; clinical efficacy; cost; cytopenia; design; human disease; immunogenicity; in vivo; induced pluripotent stem cell; nonhuman primate; novel; preclinical evaluation; progenitor; public health relevance; 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.

项目概要/摘要 人类诱导多能干细胞 (iPSC) 造血分化的最新进展 使 iPSC 衍生血液制品的临床转化更接近现实，并强调了对 开发新的动物模型，用于临床前评估的功效、安全性和免疫原性 iPSC 衍生的血液制品。由于 iPSC 可以来自预期的接受者，因此它们可以提供 产生无限数量的自体血细胞并避免 HLA 同种免疫的可能性。然而， 个性化干细胞治疗的高成本及其复杂性使其目前对广泛的患者来说不切实际 应用。已提议创建 iPSC 库作为供应 HLA 匹配血细胞的一种方法。 然而，由于 HLA 的高度变异性，使用随机供体的 iPSC 库仍然不切实际。这 建议从 HLA 纯合供体中储存 iPSC（基于单倍型的储存策略） 为细胞提供可扩展的现成免疫相容细胞供应的有效方法 疗法并最大限度地发挥干细胞库的效用。因此，开发银行 HLA 实验模型 纯合 iPSC 系并评估其免疫原性、治疗功效和安全性至关重要 未来用于制造 HLA 兼容血液制品的干细胞库的设计和实用性。在这里，我们 提议建立一个非人灵长类动物模型来储存主要组织相容性（MHC）纯合 iPSC 输血治疗线。所提出的模型将采用毛里求斯食蟹猴，它们是 来自较小的创始人群体的后裔，MHC 多样性非常有限，仅由 7 种组成 常见单倍型（M1-M7）。这提供了快速选择 MHC 纯合子和 MHC 的独特机会 血型相同的动物或通过基因筛查具有明确的 MHC 不匹配的动物。我们将 使用该模型评估 MHC 纯合 iPSC 衍生的 CD34+CD45+CD38- 的实用性和安全性 多能造血祖细胞治疗清髓干细胞后血细胞减少症 移植并检验输注来自 MHC 匹配纯合子的 imHP 的假设 iPSC 减少 HLA 同种免疫。在目标1中，我们将建立MHC纯合NHP模型 MHC 相容 iPSC 衍生血液制品的临床前评估。在目标 2 中，我们将评估功效 以及基于 MHC 纯合 iPSC 的 MCM 模型中获得性骨髓抑制疗法的安全性。 在目标 3 中，我们将评估跨界转移后对 MHC 纯合 imHP 的同种免疫反应 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 用于治疗骨髓抑制和 HLA 的纯合 iPSC 衍生造血细胞 同种免疫减少。