Replay, a company built on a portfolio of interconnected next-generation cutting-edge technology platforms that aim to solve critical problems in genomic medicine, today announced its launch with $55 million in seed financing. The newly launched “genome-writing” company has been sowing its scientific seeds in a renovated technology campus with an industrial warehouse feel—a mix of concrete and huge floor-to-ceiling windows—in San Diego, California. The freshly kitted-out building, which touts high-end finishes with a café, golf simulator area, and fitness room contained within a sleek new modern structure, seems to be the architectural embodiment of Replay. The company aims to separate technology development from products and use these core platforms to generate product companies.
Incorporated in March of 2021, Replay was co-founded by physician scientist Adrian Woolfson, BM BCh PhD, formerly Executive Vice President and Head of Research and Development at Sangamo Therapeutics; Lachlan MacKinnon, a member of the founding team at Oxford Science Enterprises (formerly OSI); David Knipe, PhD, Higgins Professor of Microbiology and Molecular Genetics at Harvard Medical School; and Ron Weiss, PhD, one of the pioneers of synthetic biology and Professor of Biological Engineering at Massachusetts Institute of Technology (MIT).
Replay’s genomic medicine toolkit currently comprises four synergistic technology platforms, including:
- a high payload capacity herpes simplex virus (HSV) vector called synHSV, capable of delivering up to 30x the payload of adeno-associated virus (AAV);
- a hypoimmunogenic iPS cell source (uCell);
- a genome writing platform (DropSynth); and
- an evolutionary inference machine learning algorithm platform for rewriting proteins to optimize functionality (LASR).
These core pieces of technology have been licensed from top US institutions. For example, the HSV platform was pulled from the University of Pittsburgh, the DropSynth technology from Harvard Medical School, and a collection of synthetic biology IP sourced from MIT. But Replay has also filed its own inventions on top of the university-licensed inventions.
“We’ve assembled a unique suite of integrated next-generation synergistic technology platforms that interlink and address the key challenges and nodes that currently limit the scope and progress of genomic medicine, and that we believe will help us to redefine the future of genomic medicine,” said Woolfson. It’s an ambitious vision and an expansive canvas, but the company has assembled a world-class team of entrepreneurs, scientists, and seasoned industry professionals to help realize their vision.
The launch is supported by an international syndicate of investors that includes KKR, OMX Ventures, ARTIS Ventures, and Lansdowne Partners. “We raised a big seed round mainly to achieve catalysts in each of our products and technologies,” said MacKinnon. “We’ve devised a way of financing focused innovation by grouping programs together. When investing in Replay, you’re investing in all the product concepts and all the relevant technologies. That appeals to a certain set of investors who aren’t keen to take a binary risk and prefer to buy into platform technologies and a portfolio. By aggregating, we can go after big challenges.”
Breaking the Mold
The overarching goal of Replay is to create an enduring company that takes products to market but remains excellent at platform development.
“Many biotech companies are not configured to be enduring,” said MacKinnon. “Instead, the companies created by most VCs have a limited lifespan and are focused on progressing a limited number of assets. We believe that the requirement to continually realize investments is inefficient for patients as know-how is continuously lost as team members move on. We prefer to create a single enduring entity that rolls out its winners directly while continuing to generate new ones”
Replay subverts the VC model, putting all the platform technology into a parent company where it can be owned and developed in a disease area-agnostic way.
“We can tackle those big problems—payload, immune silencing, assembling DNA, and understanding how to reprogram proteins—and build value in a more traditional manner through the product companies that we incorporate. These look like more traditional VC investments with a limited pipeline, defined scope, and a real focus on attaining clinical data,” said MacKinnon.
“Those entities will take the products to market, but in the background, we will continue to develop the next generation of technologies and retain the future optionality. We have a long list of product concepts to pursue beyond gene therapy as we move forward.”
By owning an entire suite of technologies, Replay reckons it can mix and match to create different product companies. And as Replay holds all the IP, licenses can be granted to any product company. To date, Replay has set up four gene therapy companies and one protein design company that leverage the components of Replay’s current platform. For instance, MacKinnon says that the big DNA assembly platform and LASR technology already have distinct product opportunities: “There are relatively near-term milestones pretty much across all of our technology platforms and products. The only way to achieve sustainable financing in biotech is to commercialize and market a product.”
Eye of the Tiger
Woolfson and MacKinnon walked me through a couple of their gene therapy companies to paint the picture of how the product companies come into focus from sketch to full-blown production. For example, in the case of the first gene therapy company, focused on monogenic diseases of the eye, Replay pulled in Professor Mark Blumenkranz, co-founder of Adverum Biotechnologies, and Professor David Schaffer, co-founder of 4D Molecular Therapeutics (4DMT)—one of the leading AAV-based ocular gene therapy companies. The eye indications were selected to leverage the ability of Replay’s synHSV delivery platform to ferry larger DNA cargos into cells or the genomes of patients than is possible using AAV.
“By offering meaningful ownership in a product company, we can attract scientist/entrepreneurs of the caliber of Mark and Dave. Replay provides a sub-license to the relevant field of the platform technology, which in this case is HSV gene therapy in the eye,” said MacKinnon. “Replay also makes a seed investment to fund the company and advance its pipeline.”
The pathology in all the diseases Replay is pursuing in its gene therapy product companies is driven by genomic stretches too large to fit into AAV. In the case of eye indications, Replay is looking at Stargardt disease, which has so far been addressed using split AAV. “All current approaches split the target gene ABCA4 into two or three pieces,” said Woolfson. “That’s inefficient both from a manufacturing and dosing perspective, and the two or three segments have then got to recombine inside the cells of the eye, which is an inefficient process.”
In the case of monogenic indications, Replay’s preference is to deliver a whole gene using synHSV, with the retention of introns enabling the preservation of natural splice functions. “We will be putting in the right gene within the right genomic structure rather than a miniaturized gene that lacks introns. It’s the perfect way to fix monogenic diseases,” says Woolfson. The cargo that can be packaged into the synHSV—up to 150 kilobases–also enables multiplex gene therapy. “In one of our programs, we’re actually putting in three genes,” said Woolfson. “You can also multiplex transcriptional regulation—using either transcriptional repressors or activators— to address polygenic disease.”
Another advantage of using HSV as the delivery vehicle is it allows for the use of natural promoters and other regulatory regions instead of synthetic ones, as synHSV has sufficient space to accommodate large stretches of DNA. “We can take a huge chunk of five- and three-prime DNA and throw it in with the gene of interest,” said Woolfson. “This enables a much more physiological type of gene correction. You never really know where the therapeutic window is, and if you don’t include the natural regulatory sequences, the correction may lead to toxicity through over-expression. As far as I’m aware, this is the first time that it has been possible to consider physiological gene correction.”
Hard as Shales
Replay was named after a concept detailed in Stephen Jay Gould’s bestselling book Wonderful Life, in which he performs a thought experiment. Starting at the origin of diverse multicellular organisms in the Cambrian found in the Burgess Shale, Gould imagines the tape of life being repeatedly rewound and replayed. The analogy here, Woolfson says, is that the genomic medicine toolkit assembled by Replay enables the company to rewrite rather than just edit genomes. Using Gould’s analogy, this amounts to an effective rewind followed by a press of the play button. Not coincidentally, the Replay corporate logo resembles one of the Burgess Shale organisms.
The concept of replaying historical evolution is especially pertinent to Replay’s uCell platform, which plans to turn cells into miniature therapeutic machines through extensive genomic rewriting. This strategy relies on a ‘hypoimmunogenic’ technology to make cells invisible to the immune system. “With CAR-T cell autologous therapy, the patient’s cells are removed, edited, and then re-introduced into the patient, which is an extremely expensive and cumbersome process,” said Woolfson. “It also takes around four to six weeks. So, there’s a substantial delay in treatment. Additionally, the volume of manufactured cells is limited, and if the manufacturing fails, the process needs to be repeated.
By contrast, in the case of the uCell platform, it is possible to anticipate a truly off-the-shelf solution. This provides for an almost infinite degree of scalability, as well as a significant reduction in cost-of-goods. Success with this would enable cell therapy to be democratized and make its use feasible in diseases beyond cancer, such as inflammatory and autoimmune diseases, as well as in regenerative medicine.
Perhaps most important of all, the uCell platform enables extensive modifications to be made to cellular genomes. In classic editing, the number of edits is typically be counted on one hand, being limited by a dropoff in editing efficiency and a risk of introducing translocations. But in the case of iPSC-derived uCells, the extent of engineering can be greatly increased.
“This enables cells to be turned into therapeutic machines by loading them up with content, whether it’s antibodies, chemokines, cytokines or whatever,” said Woolfson. “To realize the true potential of cell therapy, especially regarding solid tumors, you are going to need to do that.” Woolfson adds that this platform could make cell therapy more affordable worldwide, both for cancer and non-cancer indications, “thereby democratizing cell therapy, which forms an important part of our vision.”
Reimagining Genome Writing and Protein Design
The other two platforms that Replay is developing are DropSynth and LASR. DropSynth is Replay’s in-house genome writing platform, originally developed in George Church’s laboratory in Boston. Using bead-based emulsions, complex pools of oligos are sequentially assembled into progressively larger pieces of DNA, which Replay refers to as “big DNA”. With DropSynth, Replay expects to be able to build constructs of up to 150 kb and more in-house, and in a cost- and time-efficient manner.
“We’re currently using DropSynth to build libraries of genes up to a certain size, but we’re also working on methods to extend that and write small genomes,” said Woolfson. “Imagine if you could write an E. coli genome in an afternoon!” While Replay focuses on therapeutics, there are many other applications, including rewriting the genomes of crops of global significance such as potatoes, wheat, and maze, for example to make them temperature- and drought-resistant.
LASR is an evolutionary inference machine-learning algorithm for rewriting proteins to optimize their functionality. LASR is based on the concept that evolution tends to home in on local maxima that are globally suboptimal. That’s because proteins have to remain evolvable, and if too specialized, will not do well in the face of change. Although natural evolutionary processes have made proteins fit for purpose, the performance most proteins can be dramatically improved through a process of redesign that utilizes evolutionary information.
“If you want to increase the thermal stability of an enzyme or optimize some other aspect of its functionality, it should be possible,” says Woolfson. “We’re currently working on improving enzymes relevant to industrial processes as a proof of concept, but plan to subsequently to move into therapeutically relevant proteins, including antibodies.”
Back to the Future
But Replay doesn’t plan to stop there. “We anticipate that our unique structure will create a significant amount of technology and know-how, and we will remain poised to develop and build out the next generations of platforms, technologies, and product concepts,” said MacKinnon. “While our product companies are expected to continue to build value in the traditional sense by reaching defined clinical milestones, the capital will flow through Replay. In this sense, we act like investors in our own product companies.”
Some hints are dropped about their next platform technology, which is based on a multi-landing pad DNA integration platform for mammalian cell engineering licensed from co-founder Ron Weiss. As I pack my things from the swivel chair in the conference room that I have occupied for the past hour, I can’t help noticing Replay’s polished nature. MacKinnon reveals that everything that they have achieved to date has been obtained by working backwards from 30 years in the future.
“That’s been the long-term goal and is the reason why, even at this early stage, Replay looks so orderly and complete. We’ve already looked into the future and worked our way back!”