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Development of Intronless Expression Plasmids for Biomanufacturing of Therapeutic Proteins

  • Full or part time
    Prof S A Wilson
    Dr E Thomson
    Dr I Sudbery
  • Application Deadline
    Friday, January 10, 2020
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Therapeutic proteins such as antibodies are a successful class of biologic drug used to treat a wide range of diseases in areas such as oncology, respiratory, inflammation, autoimmunity and cardiology.
Typically, large‐scale production of such proteins for clinical and commercial therapeutic applications employs stable recombinant mammalian cell lines, such as Chinese hamster ovary (CHO) cells that are transfected with an expression plasmid encoding the antibody genes of interest. High levels of protein expression are key to the successful development and manufacture of these biotherapeutics. This can be achieved by including elements such as strong promoters, termination sequences, and introns in the expression plasmid. Synthetic or naturally occurring introns are well known to increase protein expression, compared to genes without introns. These introns are removed during mRNA processing by splicing, resulting in the translation of the correct mature protein which is then secreted into the cell culture medium. However, misplicing of these introns can lead to the expression of aberrant proteins and therefore contamination of the biotherapeutic product that needs to be removed.

Therefore, development of robust high expressing intronless systems is desirable. In this project we will combine computational approaches with engineering of CHO cell lines and plasmid expression systems to generate high efficiency host/plasmid systems for the expression of biopharmaceuticals from intronless plasmids. The project involves a collaboration between Stuart Wilson, Emma Thomson and Ian Sudbery from the Sheffield Institute for Nucleic Acids (SinFoNia; http://www.genome.sheffield.ac.uk) and a team from AstraZeneca (Granta Park, Cambridge). The successful student would be based at the University of Sheffield and receive a broad training in bioinformatic analysis, modern molecular biology techniques such as CRISPR genome engineering and gene expression analysis and would work at Astrazeneca for at least 1 month per year.

Informal enquiries should be addressed to

Applications, which should include a full C.V. with contact details and reasons for applying, should be submitted to . The closing date for applications is 10th January 2020.

Funding Notes

This 4 year studentship is funded by BBSRC and AstraZeneca and is open to UK and EU candidates.

References

Recent publications from the laboratories include: Viphakone et al, Molecular Cell (2019) v75:310; Thoms et al (2015) Cell 162:1029; Smith et al (2017) Genome Res 27:491.

How good is research at University of Sheffield in Biological Sciences?

FTE Category A staff submitted: 44.90

Research output data provided by the Research Excellence Framework (REF)

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