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Many mammalian cell lines used in the manufacturing of biopharmaceuticals exhibit high glycolytic flux predominantly channeled to the production of lactate. The accumulation of lactate in culture reduces cell viability and may also decrease product quality. In this work, we engineered a HEK 293 derived cell line producing a recombinant gene therapy retroviral vector, by down‐regulating hypoxia inducible factor 1 (HIF1) and pyruvate dehydrogenase kinase (PDK). Specific productivity of infectious viral titers could be increased more than 20‐fold for single gene knock‐down (HIF1 or PDK) and more than 30‐fold under combined down‐regulation. Lactate production was reduced up to 4‐fold. However, the reduction in lactate production, alone, was not sufficient to enhance the titer: high‐titer clones also showed significant enrolment of metabolic routes not related to lactate production. Transcriptome analysis …