Gene Therapy Process Development | Corning

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Considering everything it takes to scale up gene therapy — the platforms, the media, the surfaces, the vessels, the equipment — developing viral vector production processes comes with many challenges.

It's no surprise, then, that labs sometimes miss a few things when scaling their gene therapeutics up or out, and those oversights can set projects back. These are common pitfalls — but most researchers don't realize that they're problematic until it's far too late.

John Yoshi Shyu, Ph.D., who oversees field and internal application scientists at Corning Life Sciences, knows firsthand how one small issue with bioprocess applications can create a wide gap between outcomes and expectations in viral vector production. Here, he identifies four essential things to know about scaling gene therapy processes.

1. Scaling up is more than simple math.

Imagine you have a sedan that has four wheels and holds five passengers. If you extrapolated that capacity proportionally, you'd expect an 18-wheeler would hold around 22 passengers. Four times as many wheels means four times as many passengers, right?

Wrong. Big rigs can hold way more people than that — but that's the same logic that often gets mistakenly applied in the lab when it comes to gene therapy, Shyu says.

"Scientists often think what they have optimized on a smaller scale is going to be proportional when they scale up," he said. "But in reality, 100 percent of the time, you won't be able to take what you just optimized in a smaller setting and have success without having to revalidate the system."

That revalidation often yields a greater capacity for more dense cell growth than you might think, and that can boost production plans in the short and long terms. But, Shyu adds, you have to make sure that you create the right conditions for those cultures to thrive.

That's where gas exchange becomes critical.

2. Gas exchange require a calculated balance.

When scaling up, labs can pack more cells per cubic space. But there's a caveat, Shyu says: You have to perfect the gas exchange.

"If you pack 100 people in the same classroom versus 10 people, you better make sure that the HVAC is pumping enough air for those extra people," he said. "That's a concept that's often misunderstood when people scale up with viral vectors. Not only are you hoping for the best biological outcome, but you're also asking cells to produce at a rate that might not be supported by your existing gassing set-up."

Optimizing the gas exchange starts with appropriate conditioned cell culture media, he adds.

"Culture selection is often the biggest challenge when we help our customers troubleshoot through potential problems," Shyu said.

Access to technical field support from your supplier — which Corning offers to its customers — is vital in making these decisions.

"More often than not, it comes down to understanding the mathematics of science," Shyu said, "and that's something we love to help customers navigate."

3. Adaptation takes time.

Any process can fall short if it doesn't properly account for variables of time — something that scientists who work with adeno-associated viruses (AAV) should be particularly vigilant about as they plan and adapt their workflows with emerging tools and technologies, Shyu says.

"When you're introducing new and different technologies, cells need time to adapt to the new environment and adjust their pace of growth," he said. "And factors of feeding, circulation, and media selection can all influence the amount of time required. For example, a lab may try to save costs by reducing the amount of media, but that may stress the cells and cause them to produce fewer viral vectors, which at the end of the day actually reduces the production efficiency.

"Bottom line, not only do you have a math challenge with gas exchange and timing with cell growth, but you also have a physics issue," he added. "It just becomes more complex as you scale up."

4. Transfection missteps can disrupt production.

Transfection is a key process in viral vector production, however, it is often overlooked in process development. So, it's important to work with a partner who has enough field expertise to be able to advise you on product selection throughout the workflow — even if they're not the ones selling the product.

"Corning doesn't sell transfection reagents, but all of us who work in the field are trained and experienced scientists, and we always offer our expertise--it's just part of our consultative process," Shyu said. "It's critical to find someone with that knowledge to help you strike the right balance between transfection reagents and the desired DNA complex that you want inserted into the cells to line up the process to meet your production goals."

"Our focus is on your entire production process," Shyu added. "We want to help ensure that everything is done correctly to achieve success."