Collaborative Research: GOALI: Dynamic regulation of CHO metabolism to optimize biomanufacturing yields and quality

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Chinese hamster ovary (CHO) cells produce 60–70% of all protein therapeutics. These are among the most expensive of all drugs to manufacture. Identifying strategies for improving monoclonal antibody (mAb) production is the primary objective of this project. The metabolic pathways of CHO cells will be engineered to make this happen. Making these therapies more affordable and available to the public will improve the health and quality of life of millions of patients. This project will also provide the opportunity for students to engage in collaborative research with industry scientists, including internships at a Janssen R&D facility. Such an experience will prepare them for a career in the biotechnology industry or in a government or academic lab. Undergraduate and high-school students will also be recruited to work collaboratively on CHO cell engineering. Dynamically balancing the metabolic requirements for efficient growth and product biosynthesis in mammalian cell cultures is a key biomanufacturing challenge. The overall objective is to engineer CHO cells that dynamically regulate their central metabolism to promote maximum yield and quality of recombinant mAbs. An industrial CHO line will be engineered to promote mitochondrial respiration during production phase by controlling expression of metabolic genes with inducible gene switches. Then, the amino acid metabolism of CHO host cells will be optimized to reduce glutamine overflow and increase energetic efficiency. Finally, IgG glycan profiles will be assessed to determine how manipulating CHO sugar and amino acid metabolism impacts product glycosylation. Metabolic flux analysis will be applied to rigorously evaluate the influence of genetic alterations on host metabolism, particularly within mitochondria and pathways that supply nucleotide-sugar precursors for mAb glycosylation.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.