Immune checkpoint-engineered oligodendrocytes as treatment for multiple sclerosis - immune checkpoints play a key role in regulating hemostasis and maintaining self-tolerance, including in the human…

The National Institute of Allergy and Infectious Diseases (NIAID), part of the Department of Health and Human Services, awarded $300,000 to the University of Texas Southwestern Medical Center on September 10, 2025, under the Allergy and Infectious Diseases Research program (CFDA 93.855).

The award funds development of immune checkpoint-engineered oligodendrocytes as a cell-based therapeutic approach for multiple sclerosis. The research builds on prior work demonstrating that immune checkpoint-functionalized glial cells, produced through metabolic glycoengineering and biorthogonal click chemistry, effectively prevent and treat experimental autoimmune encephalomyelitis in mice. Two specific aims structure the work: formulation of checkpoint-engineered oligodendrocytes using stem cells and induced pluripotent stem cells to demonstrate feasibility of generating autologous oligodendrocytes for checkpoint engineering, and examination of engineered oligodendrocytes in myelin oligodendrocyte glycoprotein and proteolipid protein multiple sclerosis models. The research hypothesizes that immune checkpoint-engineered oligodendrocytes can engage autoreactive immune cells, induce T cell exhaustion and immune tolerance, and that optimal combinations of immune checkpoints produce additive or synergistic effects regulating central nervous system autoimmunity.

Place of performance is Dallas, Texas. The period of performance runs through August 31, 2027. This is a project grant (assistance type).

Immune checkpoint-engineered oligodendrocytes as treatment for multiple sclerosis - immune checkpoints play a key role in regulating hemostasis and maintaining self-tolerance, including in the human autoimmune disease of the central nervous system: multiple sclerosis (MS). We previously employed metabolic glycoengineering and biorthogonal click chemistry to bioengineer immune checkpoint functionalized mouse glial cells. We demonstrated that these immune-checkpoint engineered cells are highly effective in preventing and treating EAE in mice. Based on this exciting preliminary data, we aim to further develop this technology to improve MS treatment. Our overarching hypothesis immune checkpoint engineered oligodendrocytes (OLG) can engage autoreactive immune cells and lead to t cell exhaustion and immune tolerance. We further theorize that we can identify a highly effective combination of immune checkpoints that can provide additive or synergistic effects that regulates CNS autoimmunity. To demonstrate the feasibility of this approach, we developed two specific aims. The first aim will formulate checkpoint engineered olgs using stem cells and ipscs. This aim will demonstrate the feasibility of generating autologous oligodendrocytes for checkpoint engineering. Second aim will examine engineered olgs using MOG and PLP MS models. Our application has high potential impact on the treatment of MS. Our approach of using biomedical engineering and glycochemistry to engineer cell-based treatment is highly innovative and novel. Our work can reveal new mechanistic insights in MS and potential new treatments for MS. In the long term, our work can lead to a new class of therapeutics for MS treatment. Our proposed treatment is highly translatable. Our work can also bring new interest in the application of biomedical engineering approaches to MS.