Step into any laboratory that works with DNA, such as one creating genetic medicines, and there’s a good chance that you’ll find flasks filled with bacterial broths swirling away in oven-like incubators. These microbial breeding grounds are exploited for the exponential duplication of plasmids. These extrachromosomal rings can package foreign DNA, allowing for mass production of specific genes, such as the enzymatic components of the CRISPR-Cas systems.
When these flasks’ once-transparent serums become cloudy and chock-full of bacteria, the microbes are separated and then chemically macerated, spilling out liquid containing the plasmids. This process, much like grape-treading, is slow, inefficient, outdated, and a bit dirty. Moreover, the plasmids carry some unwanted bits of DNA, such as genes for resistance to microbes, degradation of complex organic compounds, and production of toxins and enzymes.
For decades, the manufacturing of DNA fragments has been carried out with plasmids. But with genetic medicines such as gene therapies and DNA or mRNA vaccines taking over clinical development pipelines, more and more companies are turning to enzymatically produced DNA as an alternative to plasmid DNA. Replacing plasmid DNA with enzymatically produced DNA eliminates many issues around complex or unstable sequences. It is proven to rapidly reduce timelines and costs at scale while improving the product’s quality.
Touchlight, a privately-owned biotechnology company, is “industrializing” plasmid synthesis to support the development of DNA-based genetic medicines. Based in London, Touchlight has developed a novel, synthetic DNA vector known as “doggybone DNA” or dbDNA™—a minimal, linear, covalently closed structure. This enzymatically synthesized DNA can incorporate a gene of interest up to 20 kilobases (kb), making it very flexible to support a range of genetic medicines. The synthetic DNA vector doesn’t have bacterial sequences and delivers a higher gene copy number per gram versus plasmid DNA.
Touchlight says its enzymatic production platform enables speed, scale, and the ability to target genes with a size and complexity that surpasses current technologies. Touchlight is applying dbDNA to advanced therapeutic modalities in-house and with partners. The company also provides contract manufacturing capabilities to produce dbDNA as a critical starting material for advanced therapy production through its manufacturing arm, Touchlight DNA Services. In September 2021, Touchlight increased its total funding to $125 million in a round led by Bridford Investments Limited and Novator Partners.
GEN Edge met with Touchlight CBO Tommy Duncan, PhD, to get the scoop on how the company is monetizing the synthetic DNA vector market and engaging projects beyond healthcare, such as DNA-enabled biobatteries that could revolutionize portable and off-grid power supply.
GEN Edge: How did Touchlight get to where it is today?
Duncan: Touchlight was founded in 2007 by Jonny Ohlson, an entrepreneur—not a scientist. Around the time of the human genome being sequenced and published, Jonny had the vision that some DNA technology would define this century. Touchlight was not a spin-out of a university. The core idea was that the way of making DNA was insufficient to support what was likely to be a boom in the future of a broadly defined market of genetic medicines.
DNA is made today through fermentation using plasmid DNA, where you put a circular piece of DNA into a bug, grow it in a vat, and then purify it. The way we do it at Touchlight is by using enzymes. We have an amplification enzyme and a processing enzyme that produce very high purity DNA very quickly at scale in a very simple and small footprint environment. In principle, our technology, which we call doggybone DNA (dbDNA), is capable of alleviating some of that pressure on what is a constrained supply chain of plasmid DNA today because we can make a lot of DNA very quickly and into a very high purity for clinical applications across the board in genetic medicine.
Touchlight began as a technology company, developing DNA manufacturing technology. But around 2015–16, when this market started to go towards viral vectors and, more recently, mRNA and genome editing applications, the proliferation of possible applications became obvious. So, we started to develop CDMO capability as a company, moving from being a technology innovator to being both that and delivering on contract development and manufacturing services.
We’re looking for the genetic medicine markets to adopt the dbDNA technology. The viral vector space needs a lot of DNA to make AAV vectors, for example. You need 3–4 pieces of DNA to transfect into cells to produce these factors at scale. Equally, mRNA vaccines have similar issues because DNA templates are a critical starting material. We are focused on engaging with that community, performing studies with them to prove that dbDNA is either equivalent or better at making these materials, and ultimately being the supplier or the licensor of the technology in all of these biomanufacturing applications.
GEN Edge: What are Touchlight’s revenue streams?
Duncan: The product is the dbDNA vector. There are other revenue streams, such as the services for development, and the enzymes will be a revenue stream. But fundamentally, it’s the dbDNA vector. For a client who is a viral vector manufacturer, their supply chain probably uses plasmid DNA. We look for them to purchase dbDNA in a similar way that they would purchase plasmid DNA. We would be a supplier to them. On a contracted basis, we would produce and ship the materials, and they would use it as a substitute for the plasmid DNA material.
We can make the material very quickly and may be able to alleviate that capacity bottleneck. It can take a lot of time to make your plasmid DNA today, but it is equally beneficial to use a cleaner vector. Getting rid of those antibody resistance genes is a compelling proposition to some, especially in viral vector production.
GEN Edge: Why is the product called doggybone DNA?
Duncan: The origin story of that is somewhat unclear. I think Jonny somehow came up with the idea. If you look at the schematic cartoon of the material, it is a linear vector with these pro-telomerase binding sequences at the end that looks like a doggy bone!
GEN Edge: How will Touchlight grow as a company?
Duncan: We’ve continued to invest heavily in innovation as a company. The reason is that we see this huge amount of growth potential in this space. We believe we are leaders in synthetic DNA amplification and will likely have competition in the future, and we want to stay ahead. We have a pretty large innovation team that develops new IP related to scaling of the technology and also developing novel reagents and materials for use in the dbDNA manufacturing platform as well as inventing new molecules that may have incremental benefits to things like genome editing.
We have another team that works in the research side of the business because we see a future where genetic medicine continues to expand its applications. We’ve seen mRNA vaccines, genome editing, and more things pop up recently—a new modality turns up every few months. If it’s a genetic medicine of some form, the chances are there’s an application for DNA. For example, we do a lot of in-house research on optimizing the platform for in vivo delivery for DNA vaccination, such as therapeutic cancer vaccines, where we believe this market will continue to evolve. So, we do invest quite heavily there.
Those are our pillars: the innovation and intellectual property investments as well as the CDMO operations, which, at present, include manufacturing suites for making GMP (good manufacturing practice) material. By the end of this year, we’re expanding into an adjacent facility with 11 more suites. We believe it will be the largest DNA manufacturing facility on earth by capacity. That’s mainly because you only need a minimal footprint per suite and a very low suite occupancy time: five days to make multi-gram scale GMP material in a single batch. So, you can turn these suites around very quickly—much quicker than you can do with fermentation.
GEN Edge: Is Touchlight doing any work in DNA delivery?
Duncan: There are a lot of ways to deliver nucleic acid. Lipid nanoparticles are becoming the workhorse of that industry, and they’ve been remarkably successful in delivering mRNA. When we are talking about biomanufacturing solutions associated with dbDNA, whether for making AAV or serving as a transcription template for mRNA, there isn’t a benefit to us bringing anything different in terms of the delivery of the material to the third party. Basically, they swap in the dbDNA for the plasmid DNA, and then the dbDNA produces either equivalent or better results.
That does change when we think about how to get DNA as the active pharmaceutical ingredient or the template for integration in a genome editing context into a cell or a tissue. We have collaborations with several different delivery companies, and we optimize the dbDNA for their delivery system. For example, we do primary T-cell cultures in-house to optimize our platform to support a genome editing company so that it works for them the first time.
We study needle-free delivery with the PharmaJet injection device in small and large animals. Electroporation in vivo is another application, and we have a few ongoing studies in lipid nanoparticles and comparable technologies. We aren’t a lipid nanoparticle company, but we have a number of biotech and pharma collaborations where we deliver the DNA materials. They have a lipid and then they formulate, using it as a delivery technology.
GEN Edge: Is dbDNA for clinical use only?
Duncan: We do sell dbDNA materials for research use only. Much of the feasibility evaluation work that we do and the process development and scale-up work that we do on behalf of third parties is nonclinical use of the DNA material. But most of those collaborations, they often have the ambition to be in the clinic and purchase GMP materials for biomanufacturing. Most things we do are to move from RUO into clinical applications.
We do have some non-healthcare applications that are interesting. For example, we’re a part of a grant from the UK’s Defence Science and Technology Laboratory (DSTL) and Office of Naval Research Global (ONRG) from the U.S. Department of Defense to produce bio-batteries using dbDNA. Essentially, we make DNA hydrogels with an enzyme cascade to take a readily available substrate such as sucrose or lactose and turn that into electricity. In principle, you could supplant the lithium battery in a low-resource setting with a defense capacity with one of these bio-batteries. There is some proof-of-concept experiments going on there, which is interesting and not as typical as many of the other stuff we do on the platform.
We have previously explored and developed an in vitro transcription-translation application of the dbDNA platform for a third party. We did it with Ipsen and the Centre for Process Innovation (CPI), a U.K.-based institution. It’s one of those technologies that align with how we see the world as a synthetic or enzymatic amplification company or DNA company where they’re going one or even two steps further. If you can make a synthetic DNA molecule and then do some sort of synthetic transcription and translation, you can imagine a future where that is an incredibly valuable technology. For things like making complex, very large quantities of proteins, that’s probably quite efficient.
GEN Edge: What is Touchlight’s plan moving forward?
Duncan: We want the dbDNA platform to be broadly adopted across genetic medicine wherever it has a significant value proposition to manufacturers and all of these new emerging markets where we are investing. We hope to push the envelope a little bit in the genome editing space and in vivo delivery of the DNA. We want to be a significant player in that space. We believe we have a best-in-class manufacturing technology. We can make a lot of high-purity DNA quickly using this amplification method. But it’s about deploying it into all these new and emerging markets. The exciting thing about this whole space is that these didn’t exist as markets, even when I joined Touchlight in 2015. They weren’t markets for contract development or manufacturing organization.
New things will always emerge as we build, scale, and validate the platform. The real challenge and opportunity for us are remaining at the forefront of these things as they emerge. The more our technology is adopted in these existing technologies, which are quite new, the more foresight we’ll have into these more future-looking markets as well. Ultimately, it is about adoption. It’s about the best-in-class vector DNA and manufacturing technology going forward.
GEN Edge: What obstacles stand in your way?
Duncan: It’s certainly not the market, nor do we lack applications or a value proposition for the technology, which is quite strong. We’ve done a good job of building a high-capability team, retaining talent, and financing the company. We raised a substantial financing round last year of $125 million. In that regard, it’s not something that’s limiting for us. That’s why adoption is key to the platform.
A generation of biologists works in this industry, all of whom were raised on cloning and plasma fermentation for it to be the workhorse of genetic medicines, research, and development manufacturing. It’s about generating the data, reputation, and ability to switch people’s mindsets in that regard. There are hurdles to overcome, but we are focused on bringing in novel technology.
