The discovery and implementation of CRISPR into a growing number of applications is changing the world daily, fueling the search for other nature-made ingenuities related to gene editing. These searches take researchers literally to the depths of the earth, such as deep-sea vents where some speculate life first arose, and other locations teeming with life to sample from all branches and twigs of the tree of life.
Metagenomi is a gene-editing company committed to developing potentially curative therapeutics by leveraging a proprietary toolbox of next-generation gene-editing systems to accurately edit DNA where current technologies cannot. Founded by CEO Brian C. Thomas, the company’s metagenomics-powered discovery platform and analytical expertise have revealed novel cellular machinery sourced from otherwise unknown organisms.
Metagenomi’s goal is to adapt and forge these naturally evolved systems into powerful gene editing systems that are ultra-small, extremely efficient, highly specific, and have a decreased risk of an immune response. But they are not just a platform company, as Metagenomi is using these systems to fuel a pipeline of novel medicines, and this toolbox can also be leveraged by partners. Their goal is to revolutionize gene editing for the benefit of patients around the world.
The company is coming off a string of collaboration announcements. Last November, Metagenomi came together with Moderna to combine next-generation CRISPR-based and other novel gene editing systems with mRNA and lipid nanoparticle (LNP) technologies to accelerate the development of in vivo gene editing therapeutics. Last month, Metagenomi announced a partnership with Affini-T Therapeutics, a biotechnology company unlocking the power of T cells against oncogenic driver mutations, to enable Affini-T’s next-generation ex vivo T cell receptor (TCR) cell therapies for solid tumor patients.
GEN Edge sat down with Simon Harnest, Metagenomi’s Chief Investment Officer and SVP of Strategy, at BIO 2022 to discuss the company’s strategy to become a leading force in genome editing.
GEN Edge: How is Metagenomi making an impact in the gene editing space?
Harnest: Metagenomi houses one of the largest databases of novel nucleases that are mined to develop therapies. We have identified thousands of active new gene-editing tools that we source from organisms out of samples picked from a diverse natural environment. The fundamental concept is to go out into the natural environment, take a cubic centimeter of dirt, and map out the entire genome [from the isolated bacteria]. That piece of dirt can come literally from a swamp on a California farm to a deep vent under the ocean.
Bacteria found in these samples have naturally evolved viral defense mechanisms—CRISPR nucleases. It is fascinating that these CRISPR systems can be found everywhere around us. For example, the well-known CRISPR-Cas9 system comes from a Streptococcus bacteria. Our team at Metagenomi is able to identify novel gene-editing systems from bacteria around us, based on the repeat clusters of genes that are a key marker for CRISPR enzymes. Through proprietary artificial intelligence and novel algorithms, we’ve been able to find bits and pieces of these repeat clusters and reassemble them into working nucleases. One of our lead nucleases right now comes from that deep-sea vent.
GEN Edge: What is Metagenomi’s formula for choosing candidate nucleases?
Harnest: We have access to public databases and perform proprietary sampling. Our library currently surpasses 11,000 active nucleases from over 200 novel families of nucleases that are highly differentiated from other known systems. We funnel this down into selecting lead enzymes based on several criteria. We look at the on-target activity, and then we look at the off-target effect. Safety is the first important thing to consider when advancing a nuclease.
We compare our off-target screens using industry-standard systems to look for any off-target effect genome-wide. We compare that to some known off-target sites of CRISPR-Cas9 and see how our nucleases benchmark versus those. We want to ensure that we only advance novel systems that are equal or better in this respect. When we think about the therapeutic application of our nucleases, we generally divide the landscape into two big pillars—in vivo and ex vivo. For in vivo applications, you have a different set of challenges than in ex vivo applications. For in vivo applications where delivery is key; we think about how small the nucleases are so we can package them to be delivered efficiently to different organs.
Our partnership with Moderna is very much focused on LNP delivery, but there are other delivery technologies that could broaden in vivo gene-editing applications where size matters. AAVs [adeno-associated viruses], for example, require a smaller cargo size, which is why we have developed one of the smallest base editors in the world. We have a series of very small nucleases with a size of around 400 amino acids. Compare this to Cas9, which is about 1,400 amino acids in size. When we build base editors or prime editors based on these tiny systems, they’re small enough to be packaged in an AAV, which have a cargo threshold of about 1,000 amino acids. This could broaden the therapeutic applications beyond what is in the clinic today.
So, size and precision matter. We still have to figure out if the fact that Cas9 comes out of Streptococcus (throat bacteria) matters for in vivo applications. You and I probably had a Strep throat infection before. And you may have a pre-existing immunity against a Cas9. Our systems are sourced mainly from non-human environments. The lead system from a deep-sea vent probably has never been in contact with a human being. We’ve done assays in vitro to show that there’s no preexisting immunity against our editing tool, so that could potentially lead to better persistence or not an immediate reaction in some cases, but we’re still figuring that out. These are all critical parts.
Perhaps the most important aspect for us is that the nucleases we discover all have different PAM sequences. Only having one gene editing system with one PAM sequence could be a limiting factor. The PAM sequence is like your milepost on a highway. Cas9 systems screen for a specific PAM sequence to home in on a target site and make an edit. Theoretically, the closer you are to that PAM sequence, the better you edit—the further away, the more challenging the on-target efficiency will be, and maybe more off-target effects will happen. We have hundreds of different PAM sequences within our nuclease library. So, we can select a system tailored to the specific edit we want to make without having that one restriction of a PAM sequence. That leads us to this theme of personalized genomic or genetic medicine—to pick a gene editing tool tailored to that specific target we want to go after. A good tool for target site A may not be the best tool for target site B.
We’re building this technology platform in a modular way, first to have the safest on-target efficiency across a multitude of different targets with various nucleases, whether we want to deliver them in vivo or ex vivo. Then we can use these diverse nucleases as a scaffold to build base editors, prime editors or reverse transcriptase tools. We also work on a technology called CRISPR-associated transposases (CAST). It has the advantage of the site-specificity of a CRISPR with the large gene integration of a transposon, all without making a double strand break. This is a very early technology, but we’re making significant progress there. CASTs could be extremely important in tackling more complex genetic diseases, such as cystic fibrosis or Duchenne muscular dystrophy, by replacing large cassettes of DNA with that technology.
GEN Edge: How is Metagenomi monetizing nuclease discovery?
Harnest: The possibilities are endless, going beyond human therapeutic applications all the way to synthetic biology, manufacturing and agriculture where there could be opportunities for better resource allocation through gene editing. But our passion right now is to bring this technology to patients and to develop therapies for patients in need. We are building a broad therapeutic pipeline, with an initial focus on in vivo therapeutics for our proprietary programs.
One of the targets we can disclose today is hemophilia A, which is one of our lead programs. Hemophilia A is a genetic disease caused by a faulty factor VIII gene, which can lead to severe bleedings and presents a serious unmet medical need. Our goal is to make a very specific edit in the liver, creating a targeted integration site where we integrate a piece of DNA that is the corrected factor VIII gene. The vision is to have a potential cure for this disease with our gene editing tools. That’s one of our lead programs. It’s a fascinating application of our technology.
GEN Edge: What are the milestones that Metagenomi has set for the near future?
Harnest: We’re moving several programs into non-human primate studies this year and next year. That’s the first big milestone to see how our nucleases work in larger animal models. They work well in mice models, but from mice to non-human primates and patients is a long road. However, we’re making great progress both on our own, and with our partner Moderna on in vivo applications. One of our lead programs in collaboration with Moderna is a co-development program, which will probably go into non-human primate studies next year. Our initial therapeutic in vivo applications focus on the metabolic disease space but we are also thinking beyond this in cardiovascular and CNS indications. Here we are in the early stages of target selection, nuclease selection, delivery technology selection, and then mapping a pathway towards the clinic.
Our first IND is probably within three years from now, but we constantly look for ways to accelerate our pathway into the clinic because these are all potentially curative approaches. Gene editing is such a groundbreaking technology as it carries the promise to make one edit, and the patient is fine for the rest of their life. Some of the approved gene therapy products require you to come back for an injection every quarter. It’s about $500,000 a year. A lot of these patients are diagnosed in their childhood, and they live with this for the rest of their life. Imagine having to go back to have gene therapy every quarter. That’s quite a burden on the healthcare system and the patients.
So, having a one-and-done gene edit is the dream. It’s the key for us to do what we do, but it’s a race for that aspect, too, because many companies are trying to enter a one-and-done therapy market. With our platform, where we have a library of highly efficient gene editing tools, we do not need to engineer one single tool for several years, but rather can screen and optimize the best tool within our platform in a matter of months. That’s how we quickly translate our platform into therapeutic applications in both the in vivo and ex vivo editing space.
GEN Edge: What has been Metagenomi’s funding strategy?
Harnest: The company has raised $300 million so far—a mix of partnership revenue and equity raises. When I joined, we had just completed a $75 million series A. In October, we partnered with Moderna, which also carried a cash and equity investment with it. We closed the series B round in January-February this year, raising another $175 million—one of the most successful oversubscribed B rounds in this space and in the context of one of the most difficult market environments I have ever seen.
We wanted to keep that cadence of financing for the company so that we did not have to adjust our growth trajectory as a company. When you have a once-a-year financing cadence, you can build a team. You can do things like a plan on building manufacturing. We are about to complete our GMP facility on time and on budget to make GMP-grade nucleases. That’s a huge deal for a platform company like us. Usually, young companies rely on outsourcing manufacturing, so owning that in-house, I believe, is a huge asset.
GEN Edge: What is Metagenomi’s strategy with partnerships?
Harnest: We think about the long-term aspect of the market versus our platform. I believe platforms are fundamental to making shifts in therapies rather than one-trick ponies. You can get lucky if you have a one-shot-on-goal company. But we know that nine out of ten drugs fail in clinical development. We think that true innovation and a shift in patient therapies come from breakthrough technology platforms. For example, the development of monoclonal antibody platforms made a huge lasting difference for patients, with many different disease applications. No one knew which antibody would work well, but I think companies that pushed forward real platforms were successful.
We want to be a platform that brings a paradigm shift through gene editing into therapeutics. But we don’t know out of a list of 20 targets, which will be the first to work well. It’s hard to say we’re going to scale things down and focus on one program where we have this platform and wealth of technology to do many things. We try to be very lean and prioritize what we do in house instead of partnering.
That’s a critical decision because a partner can accelerate things. Sometimes you give up crown jewels and regret it later. Sometimes a partner can greatly accelerate development that you couldn’t do on your own. We try to make those decisions very carefully without jumping at a deal for the sake of jumping at it and announcing a deal. We think about what we are getting out of that partnership and how it accelerates our therapeutic development. We look at leveraging novel delivery technologies with partnerships that are outside of our core areas of our proprietary pipeline. It’s a powerful aspect of our gene editing platform, being very versatile and partnering intelligently. It can stretch what we can do with our platform without scaling things down to save money and focus on a series of lead programs in different areas. In the future, we could also be thinking about creating spin outs into other research areas.
GEN Edge: How will Metagenomi make use of the deal with Affini-T?
We just announced our partnership with Affini-T. We believe they are one of the best teams in cell therapy development. Here, our goal is to apply our gene-editing tools in an ex vivo setting to create novel immunotherapies. The gene editing piece enables us to do extraordinary things with cells. You can make gene edits to cells to go after certain tumor targets that they otherwise wouldn’t be able to go after. Then you can make edits to have the cells persist longer. Then you can make edits to increase or dial down activity of these cells.
You can do fantastic engineering to cell therapy with gene editing in the T-cell, NK-cell, and Bcell spaces. For example, many interesting new things are happening with αβ T cells and γδ T cells, or CAR-NK cells—all these cells require gene editing. Our long-term strategy is to create a portfolio of different shots on goal within the cell therapy space. We’re not pretending that suddenly we’re oncology experts! We want to work with the best teams in the business that have been treating patients for years with cell therapies and know the tumor-associated antigens.
Affini-T goes after solid tumors with TCR T cells. It’s a massive leap from the initial kind of hematology or leukemia applications of CAR-T cells. For example, now we’re getting T cells into solid tumors. Affini-T is developing TCR T cells for tumors with KRAS, p53, and other target mutations. This type of project requires gene editing to bring that promise of TCR T-cell therapy into solid tumors. We wanted to work with the best teams, and that team knows us well. We think we can hit the ground running using our technology and potentially accelerate the pathway to the clinic there. Beyond the initial targets that are exclusive to Affini-T, we have the opportunity to enter into co-development programs in the future. This is another way we see our pipeline of gene-editing applications growing.
