Fargo, ND, is probably better known for its blizzards, floods, and eponymous TV series than its biotechnological prowess. Yet for the past 25 years, Aldevron, a manufacturer of DNA, RNA, and proteins, has grown and thrived here in the Northern Great Plains, developing products that support innovation in cell and gene therapeutics and vaccines.
Aldevron is, in fact, among the world’s largest plasmid DNA manufacturers, producing plasmids and RNAs at large scale to support various vaccines and therapies. During the COVID-19 pandemic, Aldevron supplied the plasmid DNA that provided a genetic template for generating Moderna’s mRNA vaccine, and the company continues to work with Moderna on other investigational programs in its pipeline.
“We have a very advanced backbone, known as Nanoplasmid, that addresses a lot of issues clients have,” says Venkata Indurthi, PhD, CSO at Aldevron. According to a recent review (Williams JA, Paez PA. Mol Ther Nucleic Acids. 2023; 32: 494–503), Nanoplasmid vectors have smaller backbones than traditional plasmids and permit the use of antibiotic-free selection methods, increasing “expression level and durability” and reducing “the cell-transfection-associated toxicity and transgene silencing that can occur with canonical plasmids.”
Products in development
The demand for cell and gene therapies is growing, and Indurthi doubts that it can be satisfied unless manufacturing processes are improved. “You can’t use the current workflows and manufacture personalized medicines,” Indurthi remarks. “It’s very difficult to manufacture anything in a box when there are cells involved.”
Manufacturing processes are needed that are automated and scaled up. Fortunately, such processes are becoming easier to develop now that synthetic DNA and RNA are becoming more available.
Aldevron is developing cell-free DNA, circular RNA, and novel purification strategies to serve its DNA, RNA, and protein workflows. Cell-free DNA, Aldevron’s program to make DNA synthetically, uses enzymes rather than Escherichia coli. “This has an entirely different workflow,” Indurthi emphasizes. “The benefits are in very niche areas, like personalized medicine. RNA, for example, has become very popular from a manufacturing perspective because you can manufacture a lot of RNA in a very small footprint.”
Developing synthetic DNA is an early step toward automating the manufacturing of various cell and gene therapies. “In the distant future,” Indurthi predicts, “you can think of going from digital code to DNA product within 72 hours, which would significantly shorten the development timeline.”
A key benefit is that synthetic DNA and RNA processing requires a smaller footprint than current bioprocessing methods, thus helping manufacturers do more in the same amount of space. The downside, Indurthi points out, is that synthetic DNA production “is much more expensive than E. coli manufacturing, and there are issues like fidelity that we have to address.”
“We manufacture DNA and use that to make RNA,” he continues. “We make our own enzymes, so we are controlling the entire supply chain to make RNA drug substances. Drug substances have to be packaged into lipid nanoparticles, and that becomes a drug product. Currently, our customers have to go somewhere else to get it encapsulated.” In May 2023, Aldevron announced that it intended to add encapsulation technology to its offerings. According to the company, customers that access this technology will be able to reduce their development timelines.
Central Dogma as business plan
The Central Dogma holds that genetic information flows from DNA to RNA to protein. From a biotech supplier’s perspective, these three elements are starting materials for finished products such as vaccines and cell and gene therapies. Moreover, the better the starting materials, the more efficient the scale-up of manufacturing processes—and the higher the quality of the finished products.
In keeping with this view, Aldevron began manufacturing DNA 25 years ago. It began manufacturing proteins in late 2009 or early 2010, and it began manufacturing RNA in 2017. “Now we are going into RNA drug product [manufacturing] as well,” Indurthi declares. “We basically manufacture the Central Dogma of life … or molecular biology.”
Aldevron was founded in a small laboratory at North Dakota State University by Michael Chambers, the company’s first CEO, and John Ballantyne, PhD, the company’s first CSO. Today, the company operates in Madison, WI (where it focuses on protein manufacturing), in Lincoln, NE (where it advances proprietary plasmid technologies), and in Fargo, ND (where it maintains its headquarters and manufacturing facilities).
In 2020, Chambers transitioned from CEO to executive chairman of the board, which allowed him to focus on innovation. The CEO position vacated by Chambers was filled by Kevin Ballinger, who had been executive vice president and global president of interventional cardiology at Boston Scientific. This past September, Jennifer Meade was named president after spending a year as the company’s VP/GM of the Nucleic Acids Business Unit, and is leading the company through its next phase of growth.
Soon afterward, in 2021, Danaher Corporation acquired Aldevron for $9.6 billion. It was then that Ballantyne retired from his position as CSO. A year later, Chambers was elected to the board of the Whitehead Institute.
The acquisition by Danaher helped Aldevron streamline itself. “We’ve removed a lot of waste in the system in the past few months,” Indurthi reports. “And we have reduced our lead time significantly.”
Aldevron’s U.S.-interior location is still unusual among biopharmaceutical companies. “There are a lot of advantages in the Midwest,” Indurthi points out. “For example, operating costs are lower, and large spaces are available. But from a talent perspective, there may be some disadvantages.” Many of the industry’s innovators (and potential employees) cluster around a few leading academic centers on the East and West coasts. Indurthi himself recently relocated to the Boston area, positioning him to network regularly, face to face, with many of the industry’s thought leaders.
Focus on innovation
Aldevron’s approach to innovation is centered around anticipating and meeting customers’ needs. “It’s what drives our innovation engine,” Indurthi insists. “In about 2017, only four or five companies were doing R&D on RNA. Since we were making DNA and enzymes, some of our clients asked, ‘Why not make RNA also?’ So, we innovated and built an RNA platform, and then continued to innovate to increase product quality and reduce impurities.” Indurthi spearheaded the dedicated RNA research program.
The expansion into RNA development was based not only on customers’ interest, but on the understanding that, as Indurthi says, “Gene editing is the next future of medicine.”
Since then, collaborations with some of the leaders in the field—including scientists at Moderna as well as Nobel laureate Jennifer Doudna, PhD, founder and chair of the Innovative Genomics Institute—have helped Aldevron perform at the forefront of that field.
