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

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
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-06-01 至 2020-04-30

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中文摘要
翻译
项目总结/摘要 从人诱导的多能干细胞(iPSC)造血分化的最新进展已经 使iPSC衍生血液制品的临床转化更接近现实,并强调了 开发新型动物模型,用于临床前评价的有效性,安全性和免疫原性 iPSC衍生的血液制品。因为iPSC可以从预期的接受者中获得,所以它们提供了 产生无限数量的自体血细胞的可能性,并避免HLA同种异体免疫。然而,在这方面, 个体化干细胞治疗的高成本及其复杂性使得其目前对于广泛应用是不切实际的。 应用程序.已经提出创建iPSC库作为供应HLA匹配的血细胞的方法。 然而,由于HLA的高变异性,使用随机供体的iPSC库仍然是不切实际的。的 从HLA纯合供体中储存iPSC(基于单体型的储存策略)已被认为是 为细胞免疫学提供可扩展的现成免疫相容性细胞供应的有效方法 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、治疗效果和安全性将是至关重要的 涉及用于制造HLA相容性血液制品的干细胞库的未来设计和应用。这里我们 建议建立非人灵长类动物模型,用于储存主要组织相容性(MHC)纯合iPSC 输血治疗的管路。所提出的模型将采用印度尼西亚食蟹猴, 来自一个小的创始人人口的后裔,并具有非常有限的MHC多样性,仅由七个 常见单倍型(M1-M7)。这提供了一个独特的机会,快速选择MHC纯合和MHC 和血型相同的动物或通过遗传筛选具有明确的MHC错配的动物。我们将 使用该模型评估MHC纯合iPSC衍生的CD 34 + CD 45 + CD 38- 多能造血祖细胞治疗清髓性干细胞移植后血细胞减少症 移植和测试的假设,输注imHPs来自MHC匹配的纯合子 iPSC减少HLA同种异体免疫。目的一:建立MHC纯合型NHP动物模型, MHC相容性iPSC衍生的血液制品的临床前评价。在目标2中,我们将评估疗效 和基于MHC纯合iPSC的疗法在MCM模型中用于获得性骨髓抑制的安全性。 在目标3中,我们将评估在转移至小鼠后针对MHC纯合imHP的同种免疫应答。 MHC屏障。总的来说,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衍生的造血细胞 同种免疫减少。
英文摘要
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.
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Molecular Determinants of Hemogenic Endothelium
  • 批准号:
    10187643
  • 项目类别:
  • 资助金额:
    $49.51万
  • 财政年份:
    2018
  • 负责人:
    Igor I. Slukvin
  • 依托单位:
Molecular Determinants of Hemogenic Endothelium
  • 批准号:
    9975885
  • 项目类别:
  • 资助金额:
    $49.51万
  • 财政年份:
    2018
  • 负责人:
    Igor I. Slukvin
  • 依托单位:
Nonhuman Primate Model for Preclinical Evaluation of Haplotype-Based iPSC Banking for HLA-matched Blood Products
  • 批准号:
    9276794
  • 项目类别:
  • 资助金额:
    $63.11万
  • 财政年份:
    2016
  • 负责人:
    Igor I. Slukvin
  • 依托单位:
Transplantation of MHC Homozygous Vascular Progenitors in Primates
海外基金