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

项目摘要 无胸腺患者，或那些出生时没有胸腺的人，完全缺乏功能性T细胞;这些患者 在没有功能性T细胞的情况下，将在生命的头两年内死于与以下疾病相关的并发症： 免疫缺陷。胸腺缺失有几种原因，包括22q11.2缺失（即，DiGeorge综合征）， 据估计，每3,000至6,000名活产婴儿中就有1人发生这种情况，有报告表明， 1/992）。大约0.5-1%的患者完全缺乏T细胞，称为完全缺乏。 迪乔治这些患者都需要胸腺植入物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中从儿童身上获取原发性组织， 该方法不可扩展并且受到组织稀缺的限制。此外，供应进一步受到限制， 供体和受体之间必须有最低限度的HLA匹配，这可能有助于胸腺植入后 自身免疫Thymmune Therapeutics，Inc.（“Thymmune”）在胸腺方面开发了专有见解 从多能干细胞（iPSC）分化，并利用这一知识开发基于细胞的 THY-001），其解决了与目前的治疗相关的关键问题。 治疗方法（即，组织的收集和可用性）。Thymmune团队有一个集体100+ 多年的药物开发经验，以支持这一努力。重要的是，我们以前的开发工作 结果表明，移植后，我们的胸腺上皮祖细胞（TEPs）在体内分化为胸腺细胞， 上皮细胞（TEC），形成胸腺样组织，尽管这些移植物的组成是可变的。在这 SBIR快速通道提案，Thymmune将改进其现有协议，以可扩展的方式生产TEP 和可重复的方式进行临床应用，并建立胸腺生成潜力， 用于治疗无胸腺的体内疗法。在第一阶段，我们将制定一个全面的TEPs分化方案， 悬浮条件，以使THY-001的工业放大成为可能，并得到一组可以使用的生物标志物 以确定预期用于将THY-001带入临床的法规要求的细胞产品。在第二阶段 工作，我们将测试我们根据优化方案开发的iPSC-TEPs的体内功能 在第一阶段开发。同样在第二阶段，我们将开发一个胸腺移植到骨骼肌的方案 移植由于目前的做法胸腺细胞组织治疗实验中的动物移植组织 直接进入肾包膜下，这不是临床上可行的部位。该SBIR快速通道提案将 建立TEPs商业化生产的必要方案，确定其体内功效， 并建立了一种可移植的方法，以促进THY-001，Thymmune的干细胞 衍生胸腺细胞疗法来治疗无胸腺患者。在这项工作之后，我们将测试我们的细胞产品 并为提交pre-IND和IND申请做准备。

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.