Azadyne Partnership

Biologics, also known as biopharmaceuticals, comprise a broad range of medicinal products that are produced using a living system or that contain components of a living organism. They include vaccines, antibodies, cell and gene therapies. Unlike small-molecule drugs that are synthesized chemically, biologics are typically larger, more complex and challenging to produce.

“Nearly half of the world’s medicines are biologic molecules, but they are much more costly to produce than small molecules,” says Jason Rutt CEO and co-founder of Azadyne. Prohibitive production costs are preventing many effective medicines from reaching patients. “In the UK, these costs impact the NHS budget and affect the NICE [National Institute for Health and Care Excellence] cost-benefit analysis; anything that can make these therapies significantly cheaper could bring about a real sea change in modern medicine.”

Azadyne is a venture-capital-backed spin-out from Trinity College Dublin, now headquartered in the UK. Since 2019, Azadyne researchers have been investigating various cell signalling pathways that affect protein production and immune cell activity with the aim of developing new treatments for autoimmune diseases such as multiple sclerosis.

Keen to explore the potential of manipulating the queuine transfer RNA (tRNA) ribosyltransferase pathway to increase protein translation, Jason and Tim Bourne, Azadyne’s CSO, approached Ray Owens, Head of the Protein Production UK programme at the Rosalind Franklin Institute.

“Ray and Becky Nadal, Strategic projects Manager at RFI, were incredibly helpful from the start and gave us great advice on how to test some of our hypothesis,” Jason says.

When the opportunity to apply for STFC funding to work on a collaborative project arose, Azadyne immediately got on board. “Ray’s team’s expertise in choosing the cell lines and proteins to express, their equipment and skills were invaluable in crafting a successful application,” he adds.

With the Proof of Concept grant they received, Azadyne and the Rosalind Franklin Institute were able to jointly explore whether queuine analogues could modulate the expression of recombinant proteins in a mammalian cell lines.

Queuine is a natural micronutrient produced by bacteria. Humans obtain queuine from dietary sources and gut bacteria. The eukaryotic enzyme tRNA guanine transglycosylase (TGT) incorporates this molecule into certain tRNA in all cells. Azadyne’s work on the role of the TGT pathway in protein translation, led Jason and Tim to consider if it could be applied to industrial production of proteins.

“We are always looking for ways to facilitate the production of complex proteins,” Ray says. “With this funding we were able to work with industry experts and apply our technology to test some innovative concepts.”

Ray’s team examined the effect of Azadyne’s compounds on the expression of seven recombinant proteins in transiently transfected cells. The results were very encouraging. “We didn’t expect the compounds to work as well as they did,” Jason notes.

The precise mechanisms underlying the increases in expression are not yet fully understood. “So-called ‘difficult to express’ proteins appear to misfold, which is probably the main reason why they are not produced very well,” Ray explains. “Manipulating the nucleotide content of cells may affect how RNA is handled and modulate the rate of translation, which in turn favours accurate folding,” he speculates.

The potential to enhance the production of complex proteins by simply adding a supplement to the culture media is very attractive and one Azadyne is eager to explore further.

Jason and Tim, were impressed with the effectiveness of the partnership right from the start. “We had regular calls to talk through plans and results; Ray and his team were always very open to discussing new ideas,” Jason says.

The industry partnership with Azadyne exemplifies how the Rosalind Franklin Institute’s technology can support efforts to address challenges in biotechnology. “Tapping into the way cells make proteins naturally to enhance the rate at which they are made could have a big impact on biologics manufacturing and benefit patients globally,” Jason concludes.