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DNA Script Preparing Launch of Benchtop Enzymatic Synthesizer for 'DNA on Demand'

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NEW YORK – Following about a year of testing with collaborators, DNA Script is getting ready to launch its benchtop enzymatic DNA synthesis (EDS) instrument, called Syntax, later this year, initially targeting molecular biology and genomics research labs with a high demand for oligonucleotides.

Separately, the Paris-based company, which has a second location in South San Francisco, is participating in two independent government-funded projects, in the US and France, to develop its technology for rapid vaccine development and diagnostic testing, respectively, to counter emerging biothreats. Earlier this month, DNA Script said it will receive up to $9.35 million under a $41 million contract awarded to GE Research by the Defense Advanced Research Project Agency's (DARPA) Nucleic Acids On-Demand World-Wide (NOW) program, and in January it reported a $1.6 million grant from the French Defense Innovation Agency to enable qPCR probe manufacturing on its platform.

Since it was founded in 2014, DNA Script has been working on an enzymatic alternative to standard phosphoramidite-based DNA synthesis. That chemical method has been in use for decades and is highly automated, but few institutions have established it in house. Instead, high-throughput providers such as Integrated DNA Technologies (IDT) or Twist Bioscience offer oligonucleotide synthesis as a service, often promising next-day turnaround.

And while other companies, such as Molecular Assemblies and Ansa Biotechnologies, are also working on enzymatic DNA synthesis methods, DNA Script believes it will be the first to launch a commercial instrument.

Its technology provides individual labs with the ability to make their own oligos on demand in a simpler and faster way than was previously possible, without the need for dedicated personnel or having to deal with toxic chemicals. This could potentially shorten the time of R&D projects, according to the firm, and users won't need to reveal sensitive sequences to an outside provider. While other companies, like Kilobaser in Austria with its benchtop chemical synthesizer, are also going after individual labs, DNA Script's platform will allow users to make up to 96 oligos in parallel and offer even higher throughput in the future.

The company's technology relies on stepwise DNA synthesis using a proprietary, highly engineered TdT enzyme (terminal deoxynucleotidyl transferase) that adds one nucleotide at a time, which carries a reversible terminator group, to an initiator DNA molecule that is tethered to a support. Each elongate-deprotect-wash cycle is about 99.5 percent efficient, the firm said, similar to conventional chemical synthesis. The finished oligos are enzymatically cleaved from the initiator DNA, purified, and quantified.

The first iteration of the Syntax instrument will be able to make a 96-well plate of 60-mer oligos in 13 hours and a plate of 20-mers in 6 hours, with less than 15 minutes of hands-on time, 99.4 percent accuracy, and a yield of 200 pmol per oligo, according to the firm. It also enables certain types of modifications, such as uracil and biotin. "We designed Syntax to be super user friendly," said DNA Script CEO Thomas Ybert during a presentation at the Advances in Genome Biology and Technology annual meeting last month.

Users upload their sequences to a cloud portal, where they can also access run data, and the reagent kits are designed for "plug-and-play ease of use," he said.

Within a year or two, the platform should be able to make 384-well plates of 120-mer oligos and offer additional modifications, which would enable applications such as FISH, qPCR, molecular inversion probes, and CRISPR/Cas.

In the long run, DNA Script envisages a throughput of a million oligos per run with even greater length and accuracy, opening up applications such as gene synthesis, DNA therapeutics, and protein engineering. Ybert said the company already showed proof of concept for a 280-mer oligo a year ago.

Since early 2020, DNA Script has been working with more than 30 collaborators in biotech, research, pharma, life science tools, and other areas who have been testing its oligos for applications such as endpoint PCR, qPCR, digital PCR, targeted next-gen sequencing, gene assembly, LAMP assays, FISH, and DNA storage.

Ybert said the firm has made more than 5,500 oligos for these partners so far, ranging in length from 15 to 72 nucleotides. These have included "difficult" sequences, he noted, such as a 40-mer with a 14-G homopolymer, which he said commercial chemical synthesis providers wouldn't even attempt but which the Syntax was able to make.

Internal and external performance comparisons between conventional oligos and DNA Script's have shown that the two are "indistinguishable" for "key genomics applications," Ybert claimed.

The Jackson Laboratory, for example, has tested DNA Script's oligos side by side with chemically synthesized oligos from IDT as primers for SARS-CoV-2 sequencing using the ARTIC protocol. On a poster presented at AGBT, the researchers showed that both types of primers "performed comparably," with minor differences in the coverage of individual amplicons that did not impact variant calling.

Chia-Lin Wei, director of genomic technologies at the Jackson Laboratory, said her lab reached out to DNA Script a year ago when the pandemic took hold because commercial oligo providers — including IDT, from which her group usually orders — were backlogged. DNA Script was able to provide them with ARTIC primers quickly, shipping them from France, and while they did not end up using them for their research since IDT's primers had arrived by that time, they did compare the two types of primers in the summer, finding that they yielded "pretty much similar results."

The initial batch of DNA Script's oligos required the lab to normalize the concentration and perform a phosphorylation step, but for later batches, the company included those steps, she said. Her lab is now considering additional collaborative projects with DNA Script but will likely not participate in its instrument beta-testing program.

Wei said one advantage of an in-house DNA synthesizer would be independence from service providers, which were flooded last year. Another advantage is the convenience an instrument affords for experiments that involve iterative testing and quick adjustments, instead of having to order repeatedly from an external source. However, for now, her lab is happy with the service it receives from IDT, which has returned to normal and provides her group with standard oligos with next-day turnaround, and more complicated ones — either long ones or those with modifications — within a few days.

Sylvain Gariel, cofounder and chief operating officer of DNA Script, said his firm has found that commercial vendors often take several days to deliver standard oligos, whereas the Syntax can make them the same day. But the instrument might not be the right solution for researchers who only need a few dozen oligos per month. "We're really focusing on those high-throughput customers," he said.

He also pointed out the security that comes with an in-house instrument and not having to send sensitive sequences out, which he said might be attractive to biopharmaceutical firms who don't want others to know what they're working on. While the Syntax currently does store sequences in the cloud, customers have the option to keep the instrument offline, he said.

When DNA Script can make more types of modifications, maybe at a lower cost than service providers, its platform could become attractive to additional users, Wei suggested. Also, RNA oligo synthesis is "really challenging" at the moment, she said, and being able to makes RNA oligos at a competitive cost in house could be another advantage.

Gariel said DNA Script has been making "very significant progress" on its RNA synthesis chemistry but doesn't know yet when it will become commercially available.

"We're going to launch more and more kits to enable new applications," he said, for example, for making qPCR probes for diagnostic assays. Ordering such probes from a service provider can take several weeks, he said, and DNA Script would cut down that time.

In the short term, Wei said, DNA Script might gain some market share from core facilities that offer DNA synthesis in house. "I don't think any current platform allows you to produce a 96-well plate of oligos," said John Nelson, a researcher at GE Healthcare who is collaborating with DNA Script on the DARPA project. "You can, of course, order them from one of many providers, but I don't believe you can just walk into your core facility down the hall and start a run of a plate of oligos," he said. "So even if their platform is just as accurate as chemical [synthesis], DNA Script allows DIY gene synthesis at what I assume is going to be a competitive price point."

In the meantime, DNA Script has started installing the first Syntax instruments under a beta testing program and plans to have 12 beta systems placed by the summer, the majority in the US, though it has not yet disclosed any of the testing sites.

A "soft" commercial launch is planned for this summer, which will be limited to small number of customers to demonstrate that the company can support them well and service their instruments, followed by a broader launch in early 2022. The list price of the Syntax has not been determined yet, but Gariel said that reagent costs will be "very much in line with the current price of same-day oligos from the commercial vendors."

A full commercial launch will also require the company to grow. DNA Script currently has 95 employees, two-thirds of them based in Paris, with the remainder in the US. It plans to sell its instrument directly in the US and Europe, which will require a sales force, but it will likely work with distributors in other geographies. The firm is also in the process of scaling up manufacturing, both in France and the US. Overall, it plans to hire significantly across R&D, manufacturing, and commercialization, Gariel said.

DNA Script's funds are sufficient for its current needs, "but we're always thinking about the next step," he said. Last year, the firm raised $89 million in an extended Series B funding round. Scaling commercially will require significant resources, he said, and the firm is looking into different options for additional financing.

Going forward, DNA Script is also interested in applying its technology to personalized medicine, including DNA- or RNA-based drugs and vaccines. "If you want to make a therapeutic on a patient-per-patient basis, you're going to need dedicated manufacturing," Gariel said.

The firm's recently announced collaboration with GE Healthcare, which also involves competitor Molecular Assemblies, will be a step in that direction. The goal of the DARPA-funded program is to develop nucleic acid-based vaccines that can be developed, manufactured, and deployed within a few days to counter a biothreat. Under the project, DNA Script will develop a method to assemble its oligos into genes, and GE Healthcare will put together all the technology pieces into a fully integrated solution, Gariel said.

The proof for this and all the other applications of DNA Script's technology will be whether the DNA works as intended. "That's the name of the game," Gariel said. "In the end, people don't care how you make DNA, they want it to work."

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