Programmable regulatory T cell platform for control of neuroinflammatory diseases 2310203

Abstract Introduction Inflammation is a fundamental component of immune defense but also a major driver of pathology across autoimmune, neurodegenerative, and trauma-associated diseases. Dysregulated inflammation propagates chronic tissue damage that current therapies fail to adequately control. Existing treatments rely on systemic immunosuppression or single-target biologics, which are limited by toxicity and insufficient tissue penetration. There is a critical need for tissue-targeted, dynamically controllable anti-inflammatory therapies. Methods We developed a multifunctional, programmable cell therapy platform that engineers regulatory T cells (Tregs) into living cellular pharmacies. These SMART Tregs are designed to home to disease-specific tissues, deliver anti-inflammatory disease-modifying molecules, and express biologics such as neuroprotective factors or functional enzyme replacements. We have established proof of concept for the platform in models of ALS and Alzheimer’s disease. Results Preliminary studies demonstrate our engineered Tregs can persist within the central nervous system and maintain functional activity, supporting feasibility for neuroinflammatory and neurodegenerative indications. The platform introduces three key innovations: integration of immune regulation with localized delivery, disease-context activation, and the ability to secrete persistence factors to extend therapeutic activity. Ongoing studies will evaluate disease-modifying molecule activity, in vivo efficacy, and biodistribution. Conclusion This Treg platform represents a paradigm shift in cell therapy, enabling precision immune modulation and localized therapeutic delivery across multiple disease contexts. The approach offers significant translational potential to several indications, including mitigation of neuroinflammation, immune-mediated injury, and protein replacement. This technology provides a validated, scalable cellular therapy platform ready for preclinical transition and partnership with translational stakeholders. Funding Source This work was supported by grants from the National Institutes of Health (NS102556, NS117895, and NS132666), Department of Defense (AL230089), and funds from the Center for Synthetic Immunity, Geisel School of Medicine at Dartmouth. Topic Categories Neuroimmunology (NEUR)