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DNA Script on Track for Release of Enzymatic DNA Synthesis Platform in 2022

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NEW YORK – DNA Script is expanding its operations and is on track to commercially launch its Syntax enzymatic DNA synthesis platform early next year after gathering feedback from early-access users at the Broad Institute and elsewhere.

Last month, the French company, which has locations in Paris and South San Francisco, California, raised $165 million in a Series C round that was led by Coatue Management and Catalio Capital Management. It is using its new funds to build out manufacturing capacity, accelerate the development of more enzymatic DNA synthesis-based products, expand Syntax's applications, and increase hiring. This week, the firm also said it received a $2.2 million grant from the National Human Genome Research Institute, which was awarded in September.

In advance of a commercial launch, DNA Script shipped Syntax machines to 41 academic, governmental, and commercial users as part of a targeted early-access program. Early users were spread throughout France and the US, and included the Broad Institute, Moderna, and the French Defense Innovation Agency.

Robert Nicol, senior director of technology development at the Broad Institute, was among the first to begin using Syntax and describes it as an easy-to-use device that can be quickly put into the hands of someone with little technical expertise.

"It's really straightforward chemistry," Nicol said. "It's basically this enzymatic addition, similar to what you would do with a polymerase. And that's pretty well handled by a good liquid handling robot, which is essentially what the instrument is."

Syntax grows DNA strands through a stepwise process mediated by a proprietary, engineered terminal deoxynucleotidyl transferase enzyme that incorporates nucleotides carrying a reversible terminator group. The enzyme adds nucleotides one by one to an initiator DNA molecule tethered to a support. Completed oligos are enzymatically cleaved from that initiator, then purified and quantified.

The current system can generate 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. It has a yield of 200 pmol per oligo and incorporates each subsequent nucleotide at an estimated 99.6 percent efficiency rate. The procedure takes place in water and avoids the use of toxic chemicals.

Nicol said that in his experience, Syntax-fabricated DNA has proven "absolutely equivalent" to other products that one might order.

"I think where it starts to get really exciting is [in] the making of custom probes," he said. "For example, being able to print fluorescent oligos for probes. Those can often take a long time if you order them from current commercial vendors, so the ability to print them quickly and efficiently is great."

Nicol expects that capability to come with the device's full commercial launch (his lab currently has Syntax serial number one). At the moment, his lab is using Syntax for several projects, including the development of 16S primer panels, rapid qPCR identification of selected microbes in a microbiome population survey project, and a DNA storage project done in collaboration with the Intelligence Advanced Research Projects Activity, a government agency.

For that project, Nicol uses Syntax to print oligos of up to 60 nucleotides for the retrieval of data encoded via other systems that are much higher throughput than Syntax.

"Take [a] cat picture," he said, "and imagine each pixel is an oligo and there's an address on each pixel that was translated to an oligo. If you want to retrieve a portion of the cat picture or something like that, you can print matching oligos to each pixel that's been encoded in DNA and retrieve it."

Nicol said longer oligos of 100 nucleotides or more, which he understands the fully commercialized device will be able to synthesize, will open up additional applications including gene assembly, CRISPR donor DNA synthesis, and FISH.

Sylvain Gariel, cofounder and chief operating officer of DNA Script, said that other customers are currently using Syntax for PCR and CRISPR applications, and in some cases, gene synthesis. The company is working to expand the platform's repertoire of applications to include qPCR, digital PCR, FISH, LAMP assays, DNA storage, protein engineering, and next-generation sequencing.

Other companies, such as Ansa Biotech and Molecular Assemblies, also see the potential for enzymatic DNA synthesis and are working to develop their own methods, although DNA Script says it is currently positioned to be the first to launch a commercial product.

Molecular Assemblies, which secured a $10 million investment last week, is in the process of optimizing its Fully Enzymatic Synthesis platform, with applications such as CRISPR, targeted NGS, and the assembly of both gene fragments and full-length genes. The company anticipates starting an early-access program in Q2 of 2023, followed by a full commercial launch later that year.

In an email, Molecular Assemblies stated that the company had already lined up several companies in biotech, pharma, agriculture, and the food industry to participate in the program.

Ansa Biotechnologies is also pursuing enzymatic DNA synthesis. In an email, Dan Arlow, Ansa's CEO, explained that the company is currently synthesizing oligos "longer than 170 nucleotides," that rival conventional methods in terms of stepwise yields.

"We’re already doing pilots of our DNA assembly and cloning service with select customers using oligos we purchase from existing vendors," Arlow wrote, adding that the firm will be ready to feed its own oligos into the assembly workflow by mid-2022.

DNA Script also has plans to synthesize DNA – and later RNA – for applications such as vaccines and personalized medicine, although these applications are less well developed for now

"We're interested in applications where you need to manufacture custom nucleic acids," Gariel said, which could run from future mRNA vaccines to gene therapies needed on a per-patient basis. The company noted that Syntax's "plug-n-play ease of use," which requires minimal training and approximately 15 minutes of setup time, makes it quickly deployable throughout the world, for instance to rapidly manufacture vaccines on short notice.

DNA Script is looking ahead to possible RNA synthesis, as well, although this effort remains at an early stage. RNA is less stable than DNA and therefore degrades more easily, making the process of manufacturing it more challenging.

"We've progressed faster than we anticipated," Gariel stated, "but we haven't started the product development step, and it's a bit too early to tell when we're going to have a product." He noted that DNA Script currently has a biochemistry that works "reasonably well" and that the firm sees "huge potential" in the RNA synthesis space.

Finally, DNA Script aims to make much more highly multiplexed synthesis possible through Syntax, Gariel said, adding that it plans to reveal more details in a few months. Earlier this year, the company said throughput could increase to 384-well plates of up to120-mer oligos within a year or two, and in the long run, throughput of a million oligos with even greater length could be achieved. "We are still on this timeline, with those targets in mind," he said.

In the meantime, DNA Script is expanding both its commercial and research and development capabilities, with plans to hire at least 100 people over the next 12 months, split roughly evenly between its France and US locations.

Positions in France will revolve largely around R&D and reagent manufacturing, while those in the US will be primarily in commercial operations, instrument development, and manufacturing.

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