Adoptive transfer of allogeneic murine Engineered Regulatory T cells ameliorates disease in models of ischemic stroke and acute lung injury 3688

Abstract Description Foxp3+ T regulatory cells (Tregs) are important mediators of tissue homeostasis and immune tolerance. Acute inflammatory and ischemic diseases including ischemic stroke are characterized by unchecked inflammation and maladaptive tissue-repair, making Tregs an exciting therapeutic approach. We report the efficacy of tissue adapted murine engineered T regulatory cells (mEngTregs) in the transient middle cerebral artery occlusion (tMCAO) mouse model of ischemic stroke. Briefly, mEngTregs were generated from splenic CB6F1 CD4+ T cells via CRISPR-Cas9 mediated knock-in of the MND promoter at the Foxp3 locus and culture activated before adoptive transfer. tMCAO mice treated with allogeneic mEngTregs showed enhanced sensorimotor, memory, and learning functions based on key readouts including accelerated rotarod and Morris Water Maze compared to vehicle control animals. mEngTreg transfer also resolved inflammation and improved disease outcomes in the context of the LPS induced model of lung injury, with reduced interstitial inflammation, fibrosis and improved oxygen saturation observed in treated mice. Notably, mEngTregs engrafted, and persisted, at the site of inflammation in the context of both preclinical models. Overall, the ability of mEngTregs to ameliorate disease as measured by key translatable biomarkers supports the potential for developing a potent off-the-shelf allogeneic engineered Treg cellular therapy for ischemic stroke and other acute inflammatory indications. Funding Sources Private capital: Novartis Venture Fund, Orbimed Capital, RA Capital Topic Categories Neuroimmunology (NEUR)