Viral infections remain a serious threat to the horse racing industry. In particular, equine herpesvirus 1 (EHV-1) outbreaks can have a major economic impact on high-performance horses and barns, often resulting in quarantine, abortion, and death of infected horses. Unfortunately, current vaccines and antiviral therapies provide incomplete protection and do not cure the horses from disease. Thus, there is a critical need to develop new therapeutic approaches. The goal of our project is to develop a novel platform that can be used to generate T cell therapies against viral infections and chronic diseases of concern to the equine industry.

The ability to generate T cells in culture has transformed our approach to adoptive T cell immunotherapies in humans. However, no such system is available for the horse. With funds from the Harry M. Zweig Memorial Fund, we will generate the first equine artificial thymic organoid (ATO), which will facilitate complete development of T cells from uncommitted hematopoietic stem cells and progenitor cells. ATOs are currently used in humans as (i) a tool to better understand T cell development; (ii) a diagnostic assay to determine the cause of immunodeficiencies (e.g., SCID); (iii) a system for gene editing T cells; and (iv) a platform for generating T cells that can potentially be used for universal, off-the-shelf T cell immunotherapies. However, there is currently no ex vivo system available to generate functional equine T cells. We believe the development of equine ATOs could revolutionize the field of veterinary medicine in the same way it has transformed human medicine and open new avenues for treating EHV-1 and other diseases that impact horse health and, by extension, the horse racing industry.

To accomplish our goal, I have formed a collaboration with Dr. Julia Felippe to combine my expertise in T cell development and experience working with ATOs with her resources and knowledge of equine immunology. Our plan is to first modify the current human serum-free ATO model for equine progenitor cells by transducing MS5 stromal cells with equine notch ligands and cytokines, allowing us to rigorously examine the development and function of equine T cells. Then, we will collaborate with Dr. Gerlinde R. Van de Walle and differentiate her equine induced pluripotent stem cells (iPSCs) into fully mature equine T cells to generate a universal source that can be used to produce T cells against viral infections and chronic diseases of concern to the equine industry. Lastly, we will determine how to expand EHV-1 CD8+ T cells in vitro to provide enhanced protection and improve clinical outcomes. Upon completion of our proposal, we expect to deliver a highly efficient and fully comprehensive platform for engineering T cell therapies for the horse.