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.
Public Health Relevance Statement: PROJECT NARRATIVE Patients with athymia have a complete absence of T cells due to the lack of thymus and will die within the first two years of life without thymic replacement. Current therapeutic approaches are not sustainable or reliable leading to long wait times during which time patients continue to suffer from complications associated with immunodeficiency. Thymmune Therapeutics is developing a scalable stem cell-based therapy for patients with athymia.
Project Terms: Activities of Daily Living; Activities of everyday life; daily living functionality; functional ability; functional capacity; Animals; Autoantigens; Autologous Antigens; Self-Antigens; Autoimmunity; Autoimmune Status; Biological Assay; Assay; Bioassay; Biologic Assays; Bone Marrow; Bone Marrow Reticuloendothelial System; capsule; Capsules; Cell Differentiation process; Cell Differentiation; Cells; Cell Body; Child; 0-11 years old; Child Youth; Children (0-21); youngster; Cessation of life; Death; DiGeorge Syndrome; 22q11 Chromosomal Microdeletion Syndrome; 22q11 Deletion Syndrome; 22q11.2 deletion syndrome; 22q11.2DS; 22q11DS; Autosomal dominant Opitz G/BBB syndrome; Cayler cardiofacial syndrome; Chromosome 22q11.2 deletion syndrome; Di George syndrome; DiGeorge anomaly; DiGeorge sequence; branchial arch syndrome; conotruncal anomaly face syndrome; familial third and fourth pharyngeal pouch syndrome; pharyngeal pouch syndrome; third and fourth pharyngeal pouch syndrome; thymic and parathyroid agenesis syndrome; thymic aplasia syndrome; Heart; Immune system; allergic/immunologic body system; allergic/immunologic organ system; Immune Tolerance; Immunologic Tolerance; immune system tolerance; immune unresponsiveness; immunological paralysis; Immunologic Deficiency Syndromes; Immunodeficiency Disorder; Immunodeficiency Syndrome; Immunological Deficiency Syndromes; hypoimmunity; immune deficiency disorder; immunodeficiency; In Vitro; Industrialization; Methods; Nude Mice; Athymic Mice; Athymic Nude Mouse; Organoids; Patients; Phenotype; Production; social role; Role; Progenitor Cells; stem cells; Suspension substance; Suspensions; T-Cells; thymus derived lymphocyte; T-Lymphocyte; Cell-Mediated Lympholytic Cells; Cytolytic T-Cell; Cytotoxic T Cell; killer T cell; Cytotoxic T-Lymphocytes; Treg; regulatory T-cells; Regulatory T-Lymphocyte; CD4 Cells; CD4 T cells; CD4 helper T cell; CD4 lymphocyte; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; T4 Cells; T4 Lymphocytes; CD4 Positive T Lymphocytes; Testing; Thymus; Thymus Proper; Thymus Reticuloendothelial System; Thymus Gland; Time; Tissue Therapy; Tissues; Body Tissues; Transplantation; transplant; Work; Generations; Measures; Tissue Transplantation; CD3 Antigens; CD3; CD3 Complex; CD3 molecule; OKT3 antigen; T3 Antigens; T3 Complex; T3 molecule; improved; Procedures; muscle transplantation; thymus transplantation; Site; Clinical; Phase; peripheral blood; Thymic epithelial cell; insight; Voluntary Muscle; Skeletal Muscle; Engraftment; cell mediated therapies; cell-based therapeutic; cell-based therapy; cellular therapy; Cell Therapy; Therapeutic; Genetic; Knowledge; Life; Clinic; Protocol; Protocols documentation; System; 3-D; 3D; three dimensional; 3-Dimensional; Live Birth; experience; lymphocytopoiesis; Lymphopoiesis; athymia; Animal Models and Related Studies; model of animal; model organism; Animal Model; Speed; unborn; prenatal; Reporting; Pluripotent Stem Cells; drug development; stem cell based therapy; stem cell mediated therapy; stem cell therapeutics; stem cell treatment; stem cell-based treatment; stem cell therapy; preventing; prevent; CD8; CD8B; CD8B1; LYT3; CD8B1 gene; Address; Harvest; Reproducibility; in vivo; Collection; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; 22q11.2; Development; developmental; pre-clinical; preclinical; stem cell differentiation; autoreactive T cell; self-reactive T cell; Outcome; scale up; clinical application; clinical applicability; Implant; Biological Markers; bio-markers; biologic marker; biomarker; biomarker panel; marker panel; experimental study; experiment; experimental research; Wait Time; in vivo evaluation; in vivo testing; epithelial stem cell; epithelial progenitor cell; stem cell function; progenitor cell function; differentiation protocol
