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

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.