EAGER: Transcriptome analysis of CHO cells to improve productivity and control protein aggregation

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1218345HarcumChinese hamster ovary cells (CHO cells) are used to manufacture a majority of the therapeuticproteins on the market today. In particular, CHO cells are able to express recombinantglycoproteins, including monoclonal antibodies, which require complex post-translationalmodifications. Even though CHO cells have become the new "Escherichia coli" workhorse cellline, there are still many engineering challenges that must be addressed. These challenges canbe calculated when assessing the cost to consumers of glycoprotein therapeutics ($10's to$1000's of dollars (US) per milligram with typical doses of 10's of milligrams).One major production challenge for glycoproteins is protein aggregation. Glycoproteins areprone to aggregation due to the size of these molecules, incomplete glycosylation, highsynthesis rates, and free thiols. Fortunately, bioprocess engineers have discovered interimsolutions, such as, media additives that can reduce protein aggregation in CHO cell cultures,but more efficient long-term solutions are necessary to stabilize production and reduce costs.The overall goal of this research project is to develop and enhance the toolbox for betterunderstanding protein aggregation beginning with gene expression. Factors that lead to proteinaggregation and conditions that reduce protein aggregation will be investigated by interrogatingthe transcriptome profiles developed from the transcriptome-sequencing component of thisproject. The CHO cell transcriptome will be made publicly available and characterized topromote genome-wide research in CHO cells. Transcriptome analysis will be used to identifygenes that affect and respond to protein aggregation.This project will provide a strong conceptual route for increasing the availability of therapeuticproteins and glycoproteins to the public. The availability of this additional high quality CHO celltranscriptome data to the public will allow for a commensurate community knowledge base thatwill enable all scholars the ability to contribute to our understanding of bioreactor process effectson this host cell line. Broader impacts also include the establishment and maintenance of apipeline of educated, motivated students, particularly those from under-represented minoritypopulations to undertake careers in biotechnology to meet this growing demand in the US.