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

• 批准号: 10483294
• 负责人: BING LIM
• 金额: $ 30万
• 依托单位: THYMMUNE THERAPEUTICS, INC
• 依托单位国家: 美国
• 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/10483294
• 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; 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; clinical application; differentiation protocol; drug development; epithelial stem cell; experience; experimental study; improved; in vivo; in vivo evaluation; insight; muscle transplantation; peripheral blood; pre-clinical; prenatal; prevent; scale up; stem cell differentiation; stem cell function; stem cell therapy; stem cells; thymus transplantation

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.

项目摘要 无胸腔患者或没有胸腺的患者完全没有功能性T细胞。这样的患者 将在生命的头两年内死亡，而与并发症相关的并发症的功能性T细胞 免疫缺陷。大自然有几种原因，包括22q11.2删除（即Digeorge综合征）， 据估计，在3,000至6,000例活生生中有1次发生，报告表明产前更高（如 通常是992分之一）。这些患者中约有0.5-1％完全缺乏称为完整的T细胞 Digeorge。这些患者都要求胸腺植入物恢复其免疫系统中的T细胞以防止死亡。 当前的治疗方法依赖于在心脏病手术过程中从儿童那里收集原发性组织， 无法扩展的方法受组织的限制。此外，供应进一步有限 必须在供体和受体之间最小的HLA匹配，这可能有助于胸腺后植入物 自身免疫性。 Thymmune Therapeutics，Inc。（“ Thymmune”）在胸腺中开发了专有的见解 与多能干细胞（IPSC）分化，并且正在使用这些知识来开发基于细胞的基于细胞 治疗（“ Thy-001”）针对伴侣的患者解决与当前有关的关键问题 治疗方法（即组织的收集和可用性）。 Thymune团队有100多个集体 多年的药物开发经验以支持这项工作。重要的是，我们以前的开发工作已经 表明，在移植后，我们的胸腺上皮祖细胞（TEP）在体内区分到胸腺 上皮细胞（TEC），形成类似胸腺的组织，尽管这些移植物的组成是可变的。在这个 SBIR快速提案，胸梅将根据其现有协议改善以可扩展的方式生产其TEP 以及可重现的临床应用所需的可再现方式，并确定了胸腺骨的潜力 在体内治疗丘脑的治疗。在第一阶段，我们将为TEP制定一个差异化协议 悬架条件可以实现THY-001的工业规模，并得出一组可以使用的生物标志物 为了预期将THY-001带入诊所的监管要求定义细胞产品。在第二阶段 工作，我们将测试按照优化协议开发的IPSC-TEPS的体内功能 在第1阶段开发。同样在第二阶段，我们将开发一种用于骨骼肌胸腺植入的方案 移植以来动物移植组织中胸腺细胞组织治疗实验的当前实践 直接进入肾上腺下囊，这不是临床上可行的部位。这个SBIR快速提议将 建立用于商业生产TEP的必要方案，确定其体内效率， 并建立一种可翻译的移植方法，以推动Thy-001，Thymmune的茎细胞 衍生的胸腺细胞疗法治疗丘脑患者。在这项工作之后，我们将测试我们的细胞产品 在大型临床前动物模型中，并准备提交预先印度和IND应用。