Genetic in situ engineering of myeloid regulatory cells controls inflammation in autoimmunity

Abstract

The ability of myeloid regulatory cells (MRCs) to control immune responses and to promote tolerance has prompted enormous interest in exploiting them therapeutically to treat inflammation, autoimmunity, or to improve outcomes in transplantation. While immunomodulatory small-molecule compounds and antibodies have provided relief for some patients, the dosing entails high systemic drug exposures and thus increased risk of off-target adverse effects. More recently, MRC-based cell-therapy products have entered clinical testing for tolerance induction. However, the elaborate and expensive protocols currently required to manufacture engineered MRCs ex vivo put this approach beyond the reach of many patients who might benefit. A solution could be to directly program MRCs in vivo. Here we describe a targeted nanocarrier that delivers in vitro-transcribed mRNA encoding a key anti-inflammatory mediator. We demonstrate in models of systemic lupus erythematosus that infusions of nanoparticles formulated with mRNA encoding glucocorticoid-induced leucine zipper (GILZ) effectively control the disease. We further establish that these nanoreagents are safe for repeated dosing. Implemented in the clinic, this new therapy could enable physicians to treat autoimmune disease while avoiding systemic treatments that disrupt immune homeostasis.

Keywords: Autoimmune disease; Glucocorticoid-induced leucine zipper; In situ gene therapy; mRNA.