Reprogramming therapy cell secretion capacity

About This Grant

Therapeutic cells produce proteins that aid in the treatment of disease. A promising strategy for their use is direct injection of these cells into the human body. Once established inside the body, they would be a constant source of the therapeutic agent. Low cellular production rate is the major limitation of this strategy. Increasing the secretion performance of these cells would make adoption of such strategies more practical. Natural plasma cells (PCs) have much higher antibody secretion rates that other cell types but pose cost and safety concerns. The objective of this project is to modify existing therapy-grade cells with the hyper-secreting capabilities of PCs. Educational and outreach activities will focus on training early-stage researchers. The strategy is to understand the mechanisms that drive the transition of B cells into high antibody-producing PCs and implement them in existing therapy cells. The expression of key transcription factors (TFs) and other regulatory factors will be manipulated. Methods will be developed to systematically tune the expression strengths, ratios and timing of these regulatory elements. This will make it possible to both investigate and optimize the utility of TF expression perturbations for maximizing biologic transcription, translation, post- translational processing, and trafficking through the endoplasmic reticulum. Analyses will be designed to identify combinations of TF- perturbations that maximize the functional secretion properties of cells. Methods to controllably trigger therapy cell reprogramming will also be established to address challenges stemming from growth arrest and the development of post-mitotic phenotypes. Development of this capability will enable comprehensive temporal analyses of cell adaptations and address challenges affecting the deployment scaling the production of hyper-secreting engineered cells for ultimate use in therapy. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.