Scientists from Denmark are tackling one of the biggest questions in advanced therapy manufacturing—why recombinant adeno-associated viruses (rAAVs) can’t be produced by the industry standard Chinese hamster ovary (CHO) cells. The team, from the Novo Nordisk Foundation Center for Biosustainability, has identified a set of modifications to the genetics of CHO cells, which they hope will allow them to develop cell lines that can manufacture rAAVs.
“We want to understand why CHO cells aren’t able to produce rAAVs and what’s going on inside them, and that’s why we’re doing this project,” explained Jesús Lavado García, PhD, a postdoctoral researcher at the Center.
The team has identified a series of targets for genetic modification, all related to energy metabolism. “What we’re seeing is disruption in energy metabolism in CHO cells, leading to them entering apoptosis or a senescence stage, which prevents them from producing any protein,” he added.
The aim of one student’s PhD project over the next three to five years will be to modulate these targets to understand what impact they have on cell physiology and to see if the team can get CHO cells to produce rAAVs. Lavado García feels positive about the project. The Danish team has worked with CHO cells for many years, he says, and knows it’s possible for CHO cells to survive, grow, and produce antibodies, even with only a few genes left.
The scientists will join two other research teams about whom he is aware: one who has not, to date, been able to produce rAAVs using CHO, and another who produces rAAVs by infecting CHO cells with a live virus—a process that Lavado García believes would not be scalable to industrial production.
“We’re confident that we can modify the targets identified and then have a viable cell to do rAAV production tests,” he continues. “I don’t think it’s going to be impossible—there are lots of things we can tweak and modulate. We have a huge window of opportunity.”
Lavado García hopes his academic team can aid rAAV manufacturers, who may not be able to spend three to five years working on a project with many risks.
