A novel methodology to modulate immune environment using synthetic mRNA

• Published in: The Journal of immunology (1950) Vol. 200; no. 1_Supplement; pp. 49 - 49.12
• Main Authors: Xu, Yitian, Huang, Lu, Kirschman, Johnathan L., Vanover, Daryll, Tiwari, Pooja M., Santangelo, Philip J., Shen, Xiling, Russell, David G.
• Format: Journal Article
• Language: English
• Published: 01-05-2018
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.200.Supp.49.12

As the next generation of gene therapy, synthetic mRNA therapy is known for its intrinsic advantages to avoid genomic integration that associated with DNA-based therapy, and its prolonged production of target proteins over traditional recombinant protein therapy. Synthetic mRNA therapy has been studied in various disease models including cancer, infectious disease and cardiovascular disease. However, these studies focus mainly on expressing proteins with direct therapeutic effect or antigens to elicit an immune response. It is not well established that whether synthetic mRNA can be taken advantage in cell based therapies in vivo to recruit cells of interest and modify them locally. Here we reported a synthetic mRNA based immune-modulation method, exampled by using Ccl2 and Ccl3 synthetic mRNA to recruit a certain population of monocyte in a non-inflamed manner. These recruited monocytes exhibit neither bactericidal or tissue-repairing behaviors, but stay in a neutral, non-programmed state. With additional Ifn-g mRNA and Il-4 mRNA, these cells can be polarized to different phenotypes. Furthermore, the monocytes recruited by Ccl3 and Ifn-g mRNA are able to launch the most rapid and strong superoxide burst, which demonstrates their active functionality upon proper signals. In summary, our data established a synthetic mRNA based immune-modulation system, which allows recruitment and modification of specific immune cell populations in a precise and localized manner, and more importantly, proves the concept that synthetic mRNA can be utilized in cell based therapies to replace the time-consuming and labor-demanding process of modifying patients’ own cells ex vivo and transferring back to patients afterwards.