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Horizon Discovery Begins Leveraging Vast Portfolio of Genome Editing Technology

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NEW YORK (GenomeWeb) – When gene-editing technology company Inscripta excitedly announced in July that its flagship novel RNA-guided nuclease MAD7 could indeed edit mammalian cells, it chose to make that announcement in partnership with Horizon Discovery.

After all, it was Horizon's transfection reagents and synthetic guide RNAs that were used in the in vitro and in vivo editing assays that answered one of the major questions that Inscripta CEO Kevin Ness had been hearing ever since he'd released MAD7 to the public in December 2017.

That kind of acknowledgement is the product of a lot of hard work, patience, and technological acquisition. Horizon truly began making a name for itself in 2009 when, as Sigma Advanced Genetic Engineering Labs, it produced one of the first rat models of autism. The company then introduced another seven rat models of autism at the Society for Neuroscience annual meeting in 2011.

But Horizon has surged to the forefront of the genome editing industry in the past few years. The firm acquired Dharmacon and its RNA interference technologies from GE for $85 million in July 2017, but prior to that, it also had a broad portfolio of gene editing tools and engineered cell lines as well as a number of service agreements with large customers including Illumina, AstraZeneca, Novartis, and Qiagen.

In a research note to investors in August 2017 in which he initiated coverage on the company at Outperform, Cowen's Doug Schenkel noted that Horizon had a catalogue of more than 23,000 cell lines for use in academic and biopharma research and product development, and had entered "the emerging area of higher-end, even higher-margin specialty cell lines for bioproduction and diagnostic validation purposes."

Add that to the wide array of licensing deals for editing technologies Horizon has signed over the past year, and it's easy to lose track of the variety of tools the firm now has under its control. By the end of 2017, Horizon gained full commercial rights to use ERS Genomics' CRISPR-edited cell lines to manufacture therapeutics and to identify novel genetic traits in species relevant to disease model generation and the industrial production of mouse, rat, chicken, fish, pig, and rabbit.

The firm had also built a portfolio that included assets such as recombinant adeno-associated virus editing technology from the University of Washington for non-therapeutic applications and a worldwide exclusive license from Sigma-Aldrich for the use of zinc-finger nuclease technology to engineer in vivo disease models. In July 2017, Horizon acquired the exclusive rights to a transposon-based platform with applications in bioproduction, reference standards, and therapeutic development. The intellectual property covering the technology is held by inventors from the Max Delbrück Center for Molecular Medicine, the Genetic Information Research Institute, the Paul Ehrlich Institute, and Horizon. It's based on helitrons, a type of eukaryotic transposon that can incorporate multiple copies of a DNA sequence into a genome either immediately or at a later time by reactivating the transposon machinery.

And it seems the company is starting to leverage the technology it has amassed. In addition to the collaboration with Inscripta in July, the company announced this week that it has signed a deal to collaborate with an unnamed pharmaceutical company to codevelop and make use of a novel research tool to identify and validate drug targets. Horizon will use a discovery platform owned by its partner to develop single-cell RNAseq-linked pooled CRISPR screening, and said it also plans to further develop and improve these tools to offer them to future partners as part of its research services operations.

"We're not beholden to any particular technology — we began with AAV, adopted zinc finger nucleases before CRISPR came on the scene, and then started working with CRISPR as well," Horizon's Head of Research Operations Chris Lowe said in an interview. "Our position has always been that we use the best technology, not just the first technology that we have available — we aim to be technology agnostic."

In fact, Horizon's diverse portfolio and level of expertise has not gone unnoticed by potential suitors. In May, UK-based life science reagents and tools company Abcam made a takeover offer for Horizon that valued it at approximately £270 million ($347.4 million). But Horizon rejected that bid, claiming it was being undervalued. Abcam announced its intention to continue talks with Horizon, but Horizon said that it saw "little strategic merit in the proposed combination." Abcam dropped its bid shortly thereafter.

Importantly, the firm is still on the lookout for what it can use to fill out its already broad portfolio, for technology it can use to make up for the disadvantages that are inherent to genome editing technology itself, and for what Lowe calls "CRISPR Mark 2" — an editing technology that's more advantageous than what's currently available, whether that means a better natural system or an engineered system.

"All gene editing techniques have their strengths, but they all have their limitations as well. We're in a position where we understand those strengths and limitations, and depending on what's driving a certain cell line or project, we are able to deploy the best tool or tools in combination to achieve our customers' goals," Lowe said. "We are constantly evaluating what works well and what could be improved, and trying to fill those gaps by identifying other technologies that might augment our collection."

The firm has even contemplated the idea of developing its own gene editing technology, perhaps to create bespoke CRISPR-Cas enzymes for customers who want them. But even though it has shown promise, there are also a large array of other companies working this area, Lowe noted, adding, "We are equally open to the idea of collaboration or licensing from groups who have already done the work."

The partnership with Inscripta could be an example of Horizon's strategy in this area. "Certainly, we'd like to have a good relationship with Inscripta. I think they're unique in the focus of the companies I've come across," said Horizon CSO Jon Moore. "If we could work as partners, certainly Horizon is interested in watching how the field develops, what we can do, and the appropriate level of commercial risk. We see in some possible futures that this could be quite significant for us, but it's not certain."

But it's not just the technology that makes Horizon what it is — after all, a professional driver gets more out of a Ferrari than an amateur. And when it comes to advising customers on their projects and research, Horizon's experts have the knowledge to get the most out of the tools that the company has been doing its best to collect, Lowe said.

"We've always been of the philosophy that we are experts in our field — we make people aware of the pitfalls [of engineering their own models and cell lines] because we don't want them wasting time not creating the right model," he noted. "We believe we can do it even better, but if they are going to try it themselves, then we'd rather enable them as much as possible. Now that we sell more products on the front end, it's incumbent on us to make sure that they're used effectively."

He also emphasized the collaborative nature of the work the firm does with its customers, adding that Horizon almost acts as a consultant.

"We don't want potential clients to come and say, 'We want to use CRISPR to make this model.' What we want them to do is explain what model they want so we can advise them which technologies will give them the best results and then work with them to achieve this," Lowe said. "One of our key strengths is experience. Horizon, until the Dharmacon acquisition, had been in the gene editing field for over a decade. Dharmacon has been in the world of gene modulation for nearly 20 years. So the combined organization has a huge amount of experience in the world of gene editing and gene manipulation. That is incredibly valuable."

Certainly, the future is bright for Horizon — the genome editing industry is, by many metrics, still in its early stages, and there's still a lot of technology left to be designed, developed, acquired, and applied.

"If cell therapy is going to be really big, the ability to manipulate cells and get them to do what they're supposed to do and not misbehave by going off and becoming leukemias, et cetera, is going to be very important," Moore said. "Now, there are various ways to manipulate the cell, but being able to knock DNA into particular locations is an important capability to get cells to behave as they should. Gene editing will be very important to the development of cell therapies, and so clearly we would like to bring expertise to companies [in the space]. We're interested in exploring the various ways we could deliver that capability."

More generally, what Lowe is looking to do is keep Horizon ahead of the industry, in part by giving researchers what they need to turn their ideas into new therapies. "What we're looking for is the next challenges or the next applications. It doesn't necessarily just come down to gene editing, but also gene manipulation, technologies that allow for downstream analyses — the whole package of the technology, application, and tools," he said.

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