Tessera Therapeutics CSO Jacob Rubens, PhD

Tessera Therapeutics CSO Jacob Rubens, PhD, has specialized in innovative startups, but with Tessera he seeks to transform two major fields—gene therapy and gene editing.

Just as gene therapy and gene editing began to flex their muscles in the clinic, Tessera Therapeutics emerged from stealth mode in July 2020 with a new way of fixing genetic problemsgene writing, they call it. Just six months later, the company netted $230 million in a Series B round, putting them in a comfortable position to show what they can do.

Tessera is one of a new wave of genome editing companies to emerge over the past year—other names include Graphite Bio, Scribe Therapeutics, and Excision Biotherapeutics. Over the past 18 months, Tessera’s scientists have tested thousands of mobile genetic elements (MGEs) which they call gene writers, arguably the most abundant type of genes in nature. Engineered gene writers can make every type of base-pair alteration, including simultaneous base-pair substitutions and even writing an entire gene into the genome. This is accomplished without causing disruption either at the entry or exit locations.

Turning a new technology into a drug discovery and development machine is a tall order, and the man leading the science arm of that charge is Tessera co-founder and CSO Jacob Rubens, PhD. He is also a principal at Flagship Pioneering, which is renowned for its packaged approach to launching companies, particularly biotechs. Rubens joined Flagship in 2015 as part of a venture-creation team, and previously helped to launch Kaleido Biosciences, a microbiome therapeutics company. Tessera’s head of technology development is Cecilia Cotta-Ramusino, PhD, a founding scientist at Editas Medicine.

Starting in 2016 as co-founder and Head of Innovation at Cobalt Biomedicine, Rubens invented and helped develop the company’s Fusosome Therapeutics™ platform, which combines fusogens with vesicles containing one of a variety of therapeutic payloads, including gene therapy, a gene editing protein, or mRNA. His co-founder at Cobalt was Geoffrey von Maltzahn, PhD, also of Flagship, and who is now CEO of Tessera. (In 2019, Sana Biotechnology acquired Cobalt.)

It is clear that Rubens, a microbiologist by training, has gone through these paces before. GEN Edge spoke to him to ascertain the promise in Tessera’s gene writing technology and what may be the challenges for this young upstart technology.

GEN Edge: Why go into this space when there are already so many gene therapies and gene editing technologies and products ahead of you?

Rubens: Gene therapy and gene editing have taken significant steps forward, but they also have some meaningful limitations in the way they can modify the genome, the cells they can affect, and how they are manufactured and delivered.

To name a couple of examples, gene editing using CRISPR, or other nucleases like zinc finger nucleases, TALENs, or meganucleases, all break the genome. Then the process depends on the host cell’s repair mechanisms to fix that broken DNA, which makes nucleases great at shutting genes down, but not much else. When we use these tools in human cells, it’s a drawback that they cannot instill specific changes or insert DNA into the genome.

With that in mind, a team of us at Flagship asked a simple question: “What if nature has evolved a better way to alter genomes than cutting DNA and relying on the host cell’s DNA repair pathway to fix the problem?” That simple question led us to explore the broad biology of this topic and how these pathways have evolved.

It didn’t take long before we came across mobile genetic elements [MGEs], also known as transposable elements or transposons. These MGEs are the proverbial “selfish genes.” Part of what’s called the “junk DNA,” they have evolved solely to cut/copy and paste/write DNA so as to replicate themselves. That’s in stark contrast to CRISPR and other nucleases, many of which evolved with the purpose of destroying DNA. It occurred to us that if we could use these MGEs to engineer genomes, we might be able to do things that are hard or impossible to do with nucleases.

Based on our research, we began to see a lot of potential in this field. Plus, MGEs are, by many measures, the most abundant genes in all of nature. Since the host cell is always trying to prevent them from replicating, there has also been tremendous pressure for them to evolve new, better ways to replicate. So, they are plentiful and there is amazing diversity among MGEs as well.

Others in the past have tried to use transposons as tools. But no one has yet taken a blank sheet of paper and said, “What is the best way to use these MGEs to create a breakthrough technology?” That is the question that eventually led to Tessera.

GEN Edge: How did you go about developing the platform?

Rubens: When we started the company there were many potential directions we could go. But we had ideas about three specific things we wanted to accomplish, and I’m happy to say we have made progress on all of them,

First, we wanted to be able to integrate DNA into the genome without making double-stranded breaks or relying on host pathways. We wanted this capability to integrate adeno-associated viruses [AAVs] into the genome of cells in the body. AAVs don’t normally do this, or you don’t normally want them to. But the fact that they don’t integrate limits their applications, especially in tissues with dividing cells. So we looked for classes of MGEs that could efficiently write DNA into the genome at specific sites. And we have shown that that is possible.

We also wanted to do away with delivering DNA completely—just deliver RNA to a cell and, by doing that, add a new gene into the genome, thereby reversing the central dogma that DNA makes RNA makes proteins. We’ve done that as well but with a different class of technology, which we refer to as our RNA gene writers. This is possible because we can deliver into the cell an mRNA that codes for a gene writer protein and a non-coding gene writing RNA template.

The third function we wanted was to be able to rewrite the genome and instill specific substitutions, insertions, and deletions anywhere we wanted in the genome. We achieved that by engineering yet another class of MGEs related to the RNA gene writers.

Accomplishing all of those feats required a platform—or a research engine as we call it—to search for, understand, and evaluate the activity of MGEs in the human genome. To achieve that, we start with a computational approach that pulls in data from various sources, which we can use to identify the sequence of MGEs. Then, using additional computational approaches, we can identify good candidates for particular functions we want our MGEs to have. Specifically, we look for MGE active sites and domains that we believe will have the right type of biochemical activity.

With that data in hand, we pick candidates to test in human cells. Then we synthesize DNA de novo, transfect it into human cells, and then measure the efficiency, specificity, and fidelity with which we can modify the genome using state-of-the-art high-throughput nucleic acid assays. That gives us a starting point. But then we go beyond natural evolution and do directed evolution to create improved gene writers that are adapted to human cells and do things they didn’t naturally evolve for. That’s where we are now.

We have many gene writers that can enable us to create drug candidates, and we are beginning to think about the clinic and actually making medicines. While we are not disclosing the targets yet, we are very likely to begin with genetic disease and oncology because there are well-defined targets and a very significant unmet need. But we have mapped out a broader range of areas, and we are ultimately headed toward others including cardiovascular, neurodegenerative and maybe even, someday, infectious disease.

GEN Edge: What were Tessera’s growing pains like? And where do you anticipate the steepest hurdles?

Rubens: It’s always hard to start a new company! Fortunately Flagship has professionalized the practice of entrepreneurship, especially in the biotech and life sciences space. An important feature of Flagship companies is that we do very challenging science, and Tessera is no exception. Our science is “beyond what’s come before,” which makes it hard, but because of that we can attract amazing scientists. Work at Tessera isn’t the typical translational job; we are truly creating something new. We were pleasantly surprised at the strong interest of people who had worked at other gene editing companies and who were now attracted to the approach we were taking. After hiring a fantastic group of core scientists at Tessera, everything else has followed.

Of course, the genetic medicine field is relatively young and we still have things to learn. But an advantage that we have at Tessera is that we don’t rely on any sort of viral vector. Our technology operates inside the cell. So, we have a lot of flexibility in how we deliver therapeutics, and we actually consider viral vectors as nothing more than a delivery vehicle. That doesn’t mean we don’t still have issues to grapple with, like which tissues they go to or what doses to use. But we are hoping to focus on the intracellular part of gene writing and build off of the delivery vehicles others have developed.

We are fortunate to have just raised over $230 million from a fantastic group of investors that shares our long-term goals and understands the resources we need to get there. While we are standing on the shoulders of the tremendous body of work done for gene therapy and gene editing, we are on the frontier at Tessera in developing a new category—gene writing. Our immediate goals are to start investing in a therapeutic development team and manufacturing team. With manufacturing, the ideal is to control everything yourself, but that’s not always possible. Still, we are in the fortunate position of having sufficient financing that we have plenty of choices.

We are at the very forefront of a frontier. Medical genetics is moving in the direction of diagnosing disorders earlier and earlier, and we think that’s the future for genetic therapies too. Our vision is that children born with genetic diseases will grow up without any sign they ever had anything wrong with them. They won’t become people living with a disease, rather, they will be people who had a disease when they were young, but have no sign or memory of it since that. We are building the tools and the platform to achieve that vision. That’s a big motivator for me and I think that’s what attracts many other people to Tessera as well.

Malorye Branca is a Boston-based contributing editor to GEN Edge.