Development of a stem-cell derived thymic cell therapy to treat patients with athymia

开发干细胞衍生的胸腺细胞疗法来治疗无胸腺患者

基本信息

批准号：
10609940
负责人：
BING LIM
金额：
$ 28.67万
依托单位：
THYMMUNE THERAPEUTICS, INC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-15 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10609940
关键词：
22q11.2 3-Dimensional Activities of Daily Living Address Animal Model Animals Autoantigens Autoimmunity Biological Assay Biological Markers Bone Marrow CD3 Antigens CD4 Positive T Lymphocytes CD8B1 gene Cell Differentiation process Cell Therapy Cells Cessation of life Child Clinic Clinical Collection Cytotoxic T-Lymphocytes Development DiGeorge Syndrome Engraftment Generations Genetic Harvest Heart Helper-Inducer T-Lymphocyte Immune Tolerance Immune system Immunologic Deficiency Syndromes Implant In Vitro Industrialization Knowledge Life Live Birth Lymphopoiesis Measures Methods Nude Mice Organoids Outcome Patients Phase Phenotype Pluripotent Stem Cells Procedures Production Protocols documentation Regulatory T-Lymphocyte Reporting Reproducibility Role Site Skeletal Muscle Small Business Innovation Research Grant Speed Suspensions System T-Lymphocyte Testing Therapeutic Thymic epithelial cell Thymus Gland Time Tissue Therapy Tissue Transplantation Tissues Transplantation Wait Time Work athymia autoreactive T cell biomarker panel capsule cell motility clinical application differentiation protocol drug development epithelial stem cell experience experimental study improved in vivo in vivo evaluation insight manufacturing scale-up muscle transplantation peripheral blood pre-clinical prenatal prevent scale up stem cell differentiation stem cell function stem cell therapy stem cells thymus transplantation

项目摘要

PROJECT SUMMARY Athymic patients, or those born without a thymus, have a complete absence of functional T cells; such patients will die within the first two years of life without functional T cells from complications associated with immunodeficiency. There are several causes of athymia, including 22q11.2 deletion (i.e., DiGeorge Syndrome), which is estimated to occur in 1 in 3,000 to 6,000 live births with reports suggesting even higher prenatally (as frequent as 1 in 992). Roughly 0.5-1% of these patients have a complete lack of T cells called Complete DiGeorge. These patients all require a thymic implant to restore T cells in their immune system to prevent death. Current treatment approaches rely on harvesting primary tissue from children during open-heart procedures, an approach that is not scalable and is limited by scarcity of tissues. Moreover, supply is further limited as there must be minimal HLA matching between donor and recipient, which may contribute to post-thymus implant autoimmunity. Thymmune Therapeutics, Inc. (“Thymmune”) has developed proprietary insights in thymic differentiation from pluripotent stem cells (iPSCs) and is using this knowledge to develop a cell-based therapy (“THY-001”) for patients with athymia that addresses the key issues associated with current treatment methods (i.e., collection and availability of tissues). The Thymmune team has a collective 100+ years of drug development experience to support this effort. Importantly, our previous development work has shown that upon transplantation, our thymic epithelial progenitor cells (TEPs) differentiate in vivo into thymic epithelial cells (TECs), forming thymic like tissues, though the composition of these grafts are variable. In this SBIR Fast Track proposal, Thymmune will improve upon its existing protocol to produce its TEPs in a scalable and reproducible manner necessary for clinical applications and establish the thymopoietic potential of this therapy in vivo for the treatment of athymia. In Phase I, we will develop a differentiation protocol for TEPs in full suspension conditions to enable industrial scale-up of THY-001 and derive a set of biomarkers that can be used to define the cell product in anticipation of regulatory requirements for taking THY-001 into the clinic. In Phase II work, we will test the in vivo function of the iPSC-TEPs that we have developed following our optimized protocol developed in Phase I. Also in Phase II, we will develop a protocol for thymic engraftment in skeletal muscle transplantation since current practices for thymic cell tissue therapy experiments in animals transplant tissue directly into the subrenal capsule, which is not a clinically viable site. This SBIR Fast Track proposal will establish the necessary protocols for commercial production of TEPs, determine their efficacy in vivo, and establish a translatable method for transplantation to advance THY-001, Thymmune’s stem-cell derived thymic cell therapy to treat patients with athymia. Following this work, we will test our cell product in large pre-clinical animal model and prepare for submission of pre-IND and IND applications.

项目概要无胸腺患者或出生时没有胸腺的患者完全缺乏功能性 T 细胞；如果没有功能性 T 细胞，患者将在生命的头两年内因以下并发症而死亡：无胸腺症有多种原因，包括 22q11.2 缺失（即迪乔治综合征）、据估计，每 3,000 至 6,000 名活产儿中就有 1 人发生这种情况，有报告表明产前发生率甚至更高（如这些患者中大约 0.5-1% 拥有完整的 T 细胞，称为“完整” DiGeorge：这些患者都需要胸腺植入来恢复免疫系统中的 T 细胞以防止死亡。目前的治疗方法依赖于在心脏直视手术期间从儿童身上采集原代组织，这种方法不可扩展，并且受到组织稀缺的限制，而且供应也进一步受到限制。供体和受体之间必须具有最低限度的 HLA 匹配，这可能有助于胸腺后植入 Thymmune Therapeutics, Inc.（“Thymmune”）在胸腺领域拥有专有见解。多能干细胞 (iPSC) 的分化，并利用这些知识开发基于细胞的针对无胸腺症患者的疗法（“THY-001”），解决了当前与无胸腺症相关的关键问题 Thymmune 团队共有 100 多种治疗方法（即组织的收集和可用性）。多年的药物开发经验支持了这一努力。研究表明，移植后，我们的胸腺上皮祖细胞（TEP）在体内分化为胸腺上皮细胞（TEC），形成胸腺样组织，尽管这些移植物的成分是可变的。 SBIR 快速通道提案，Thymmune 将改进其现有协议，以可扩展的方式生成 TEP 和临床应用所需的可重复方式，并确定该药物的胸腺生成潜力在第一阶段，我们将开发一种完整的 TEP 分化方案。悬浮条件，以实现 THY-001 的工业放大并衍生出一组可用的生物标志物定义细胞产品，以预期 THY-001 进入临床阶段的监管要求。工作中，我们将测试我们按照优化方案开发的 iPSC-TEP 的体内功能在第一阶段开发。同样在第二阶段，我们将开发一种胸腺植入骨骼肌的方案自从目前在动物移植组织中进行胸腺细胞组织治疗实验的实践以来，移植直接进入肾下囊，这不是临床上可行的部位。建立 TEP 商业生产所需的方案，确定其体内功效，并建立可转化的移植方法以推进 THY-001（Thymmune 干细胞）衍生胸腺细胞疗法用于治疗无胸腺症患者。在这项工作之后，我们将测试我们的细胞产品。大型临床前动物模型，并准备提交预 IND 和 IND 申请。