The mRNA molecule has played a transformational role in recent years in helping contain the spread of SARS-CoV-2, but a less known molecular sibling has been largely overlooked in the past by biotech entrepreneurs and industry. The molecule is known as tRNA (transfer RNA) and its starting to have it’s share of the limelight. tRNA is a small RNA molecule that plays a fundamental role in protein synthesis, acting as a bridge between mRNA and the growing chain of amino acids that constitute a protein. However, things do get lost in that critical translation and errors in the way the amino acid chain is assembled can lay the foundations for disease. This is where Alltrna, an emerging biotech with $109 million in Series B funding is channelling its scientific focus and resources. At its helm is CEO Michelle Werner, a pharmaceutical veteran with a proven track record in developing oncology drugs now turning her sights to the vast sea of diseases that could benefit from tRNA technology. Inside Precision Medicine’s editor in chief, Damian Doherty, spoke to Michelle about her career, her motivation to lead this company, and what rare disease means to her on a personal level.
Q: I see you’re working for both Flagship and also Alltrna—how do you manage to juggle both roles?
Well, I’d say my predominant focus is really as CEO of Alltrna. So day-to-day, it very much is about building and operating the company that’s focused on transfer RNA (tRNA) but Alltrna does fit within the Flagship Pioneering ecosystem. And so my dual role also, I guess, symbolizes or signifies the role that I play in helping to contribute to the broader success of the ecosystem at large.
Q: Flagship has as a number of RNA-focused companies in the portfolio, can you touch upon that?
Yes, so probably the best known is Moderna, which has been focused on mRNAs over the past decade. There’s quite a lot of experience in RNA therapeutics, which is fantastic. So being part of an ecosystem that has been on the forefront … we’re really understanding the biology of RNA and then bringing them forward into novel therapeutics is something that we feel very fortunate to be able to have access to and certainly helps contribute to the work that we’re doing here at Alltrna.
Q: mRNA is certainly having its moment. Has that been helpful in paving the way for approaches like tRNA?
We definitely are a distinct entity at a turnout, but I say this all the time: we absolutely stand on the shoulders of giants. When we think back to the work that Moderna’s done over the past decade, really understanding the biology, how to decipher the biology and program it into therapeutics, really understand how to then apply those therapeutics in a clinical capacity, how to deliver oligonucleotides is really important. So those are all things that we feel as though we have the benefit of not having to start from scratch because there are others who have played a role in advancing them already. Now, nobody’s done it with tRNAs before and certainly in the ways that we’ve been doing it at Alltrna. And so there’s lots of nuances and learnings that we’ve had to develop all on our own, but certainly we hit the ground running because of the knowledge that has been gained in the mRNA space over these years.
Q: So tell me a little bit about your career transition. What was the drive to shift from a largely oncology-focused career to rare diseases?
Yes, I’d say it’s been about 20 years or so that I worked in the oncology space in a variety of different roles and capacities in pharma. I’ve had the privilege of being able to work on a number of novel agents, both when it came to targeted therapies as well as immunotherapies, and launched a number of those. I think it’s been about a dozen or so launches that I’ve had during my career. And when I think back to when I entered the oncology field multiple decades ago, the standard of care, irrespective of which type of cancer you had, was chemotherapy. We’ve made a tremendous amount of progress during that time. So I reflect on the last two decades and I feel like there’s more work that we still need to do in the oncology space, but we’ve been able to extend survival rates significantly during this time.
I’ve always loved being in that setting and feeling as though I’ve had the opportunity to have a significant impact on patients. And patient impact is always something that’s driven me in my career. About three and a half years ago, my family found ourselves sort of thrown into the rare disease community when my son, who was 10 at the time, in fact it was actually his 10th birthday, was diagnosed with Duchenne muscular dystrophy, which is a really devastating diagnosis of progressive neuromuscular disease. And I was really shocked to learn that the standard of care wasn’t really great. There were some clinical trials exploring some innovative therapies, but not a lot. And my son wasn’t eligible for any of them.
It really has inspired me to think about how I channel all the experience that I’ve built in my career over these decades to date, contributing to oncology care, to help me look at the next 20 years and see how I’ll be able to play a small role in changing the outcomes for patients with rare diseases. And that’s a massive motivator for me. So when I was first introduced to Flagship Pioneering and hearing the story of Alltrna, to me it just felt like a beautiful marriage given my personal passion to this space, coupled with being able to work with this exciting technology. I could really see the potential to make a huge difference and I knew I wanted to be a part of it.
Q: Can you talk about the genesis of Alltrna and where the science and technology was born?
It was really about five years ago now where Flagship Pioneering started to ask one of their, I’d say very famous, what if questions, which has given birth now to a number of different companies. And we asked ourselves, what if we could really alter the protein translation process by leveraging the tRNA? We knew what tRNA does but maybe just for the purposes of this discussion, I’ll just remind you of your Biology 101 days.
So the tRNA plays a really critical role in protein translation. It really is where the anticodon of the tRNA precisely matches the codon of the mRNA, which codes for all the amino acids that make up proteins. And so the tRNA reads those instructions for which amino acid comes next and then actually finds that corresponding amino acid within the cytosol and then transfers that corresponding amino acid to the growing polypeptide chain. And the result is full-length functional proteins, which is of course what we all need to have cellular function and life in and of itself. So that’s the role of the tRNA.
Now, when we thought about how to alter the protein translation process, we really started with an understanding of various different types of mutations that occur, because the code on the mRNA is not always precisely correct and mutations do occur. And there are many different types of mutations that lead to genetic diseases, but there’s one type of mutation that’s called a nonsense mutation, or where there’s a premature termination codon. And what happens in that case is that instead of a codon for an amino acid on the mRNA, it codes instead for a stop. There’s no natural tRNA that can read a stop codon. And so the result is a premature termination of the protein translation process. So you either get a shorter protein than normal or a missing protein altogether, and that is what causes diseases. So we really thought about tRNAs then to address these premature termination codon mutations. And that’s where Alltrna came about, because we all then started to say, well, what if we could engineer tRNAs that understood these premature termination codons? So instead of coding for a stop, it actually transferred what should have been the precisely correct amino acid and restored that protein translation process in order to have a full-length functional protein, which is precisely what patients need to address the disease in that setting.
Q: Have we simply overlooked this as a foundational process?
I think it was overlooked. I think we understood what the role of tRNA was, but the reality is that we didn’t actually have the tools that were needed to really understand how to unlock the understanding of how tRNA performs into something else. And when Alltrna began, we had to develop an entirely new toolkit to really understand how to quantify and measure tRNAs in the system, how to differentiate engineered tRNAs from those that naturally occur. And so all of those were tools that had to be generated, which is some of the early work that our team did in those early years.
Q: What is Alltrna doing that’s differentiated from some of the other companies in this space? What’s your approach and how does your machine learning platform work?
I think it’s great that there’s a couple of other companies that are looking at the tRNA space, because I think it lends credence to the idea that this might be an interesting new modality for patients. We’re taking a very broad look at tRNA biology. First of all, what we’re doing is engineering tRNAs that are not just engineered for the 76-nucleotide plus or minus sequence that makes up those tRNAs. But we’re also using chemical modifications on those sequences in order to enhance different therapeutic properties like stability and activity and specificity and those types of things, which will be really important as we work towards the clinic. So, we have a very robust machine learning engine that helps us to understand the predictive rules of which sequences are going to work best and which chemical modifications are also going to be truly important.
And we’ve shown data, which we presented earlier this year, that by enhancing or optimizing for sequences and optimizing for chemical modifications, we’re able to substantially improve the activity of our engineered tRNAs over endogenous tRNAs. And we do that because our machine learning tools can really help enable the excellent scientists that we have. So that’s something that we do that’s robust and unique. I spoke specifically about engineered tRNAs for nonsense mutations, but we also think there’s a role to play for engineered tRNAs for other types of mutations like missense and frameshift, and we’re looking at that as well. But then also more broadly with the biology, there’s an understanding that tRNA pools and tRNA fragments may also play an important role in addressing a number of other types of patients as well. And that’s something that we’re interested in exploring. So altogether, we’re differentiated across those domains, and I think it makes some of the work that we’re doing super exciting.
Q: What are the therapeutic opportunities for tRNA? Are you casting your net wide?
I think that’s one of the unique features about tRNA, because the role of the tRNA is the same. No matter which gene, no matter which protein is being encoded for, it does the same job. We take a very different look at the world. So the conventional way of looking at patients is by that specific disease, which is really classified by the gene that’s affected or their clinical phenotype. But all other modalities look at each of those diseases on a disease-by-disease strategy. And keep in mind, when it comes to the world of rare diseases, there are over 6,000 of them and they affect 300 million people around the world. So it’s a huge number of patients across a big number of diseases. And if we tackle them in a disease-by-disease strategy, we are going to hardly make any progress in those 6,000 diseases in our lifetimes for sure. And probably in the lifetimes of hundreds of other people.
What’s super cool about the tRNA is that we think very differently about patients—not by the disease classification, but we actually reclassify patients by those underlying mutations that are common across all those different diseases. And that’s where we have that unique possibility of using a single engineered tRNA that can address hundreds if not thousands of different diseases because we see the same mutations over and over and over again from disease to disease. And that allows us that opportunity to address so many more patients across so many different diseases that would never have had the opportunity to see an innovation in their lifetime. And I think that’s an amazing, amazing possibility to work towards.
Q: I know you’ve said in the past you’d like to make what’s clinically and economically unfeasible feasible. Obviously, it’s a little too early to talk about the financial aspects of developing a therapeutic but one senses you’re going to try and make these therapeutics more accessible and affordable.
Well yes, you’re right, it’s definitely too early to talk about cost, but what I would say is really important is when companies assess the opportunity or evaluate the opportunity that they can unlock, they look at the numbers of patients who might be able to benefit from a novel therapy moving forward. And of course, there has to be a certain number of patients that could benefit in order to justify the development costs that go into the process, because in the tRNA and in the rare disease setting, especially in ultra-rare diseases, you may not have a huge number of patients in any one of those single diseases that would allow for that return on the investment. However, when you can unify patients across those different diseases, so that it doesn’t matter if you’ve got only a handful of patients in one disease, when you can bring those patients together that have those common mutations across those different diseases, all of a sudden the opportunity that you can unlock is much, much bigger.
So you can really justify the investment that it takes in order to be able to bring this discovery and development forward. And that’s what I think is really important, because unless we solve that challenge, we’re going to have so many patients that will continue to be unserved as they are today. Right now, there are thousands of different diseases where there’s not a single clinical trial ongoing, or an interventional clinical trial I should say, because just patient numbers don’t justify that type of investment. But at the end of the day, these are real people who need real medicine in order to address their disease. And a tRNA that can unify those patients across a number of different diseases may allow for that opportunity. And that’s what we’re really all about at Alltrna. We’re really helping to bring that forward. And we do think that can be a much more efficient development process as a result. And we also believe with this approach, you can do clinical trials that don’t have one disease in them. They might have many different diseases in them like a basket trial, and of course you can do a basket trial that has different diseases together. That in and of itself is an efficiency in the process.
Q: What defines Alltrna in terms of its corporate culture and indeed how are you looking to lead the company in line with those values?
So I’ve been with Alltrna for about a year and a half. I joined shortly after the coming out party for Alltrna. I would say first and foremost, what I think is really important, and maybe not surprising to hear from this conversation so far, is I’m a very mission-driven, purpose-driven type leader. We’re thinking about patients first. In fact, one of my favorite corporate values for Alltrna is “Patients Deserve Better.” And we all really rally behind that idea. So that’s what I think is first and foremost. But I also think that we’re steeped in doing some great science and being authentic in our leadership. For me, it’s really all about building a culture where people can bring their best selves to work and to the table, because I think that’s how we get the best thinking out of everybody. And it’s the best thinking from the team collectively that is going to help innovate and solve problems and do all kinds of things like that that are really crucial when you have a brand-new modality that’s never been done before and you’re trying to bring that forward.
So that’s a lot about who we are and how we operate as a company. I’d say in the last year and a half, we’ve made a tremendous amount of progress with our platform. When we first started, nobody had ever chemically synthesized a 76-nucleotide molecule before, and we were amongst the first to do that. And then to do the chemical modifications on top of that. We’ve just this past year announced our series B raise, which is great. So it’s the first time that we’ve been able to recruit external investors to Alltrna. They have a huge amount of conviction for the work that we’re doing, and that’s really exciting for us. And now it’s really about moving our platform forward in such a way where we can advance the most promising of our molecules, our engineered tRNAs, and advance them towards the clinic. So we’re very focused on being able to demonstrate the impact that we have in that setting, and that’s what we’re looking forward to achieving next.
Q: What are the business goals for 2024?
As I mentioned, we’ve already shared some exciting data this past year but as we look forward, I think we’ll be talking more about the advancements or the progress we’re making with our advanced candidates. Watch this space as we move forward, but we’re starting to talk a lot about what we call stop codon disease, which is the patient population that we believe are in line of sight for us—all patients who have a genetic disease that stems from a stop codon—that’s really the target for us. So, you’ll be hearing more from us about how it is that we’re looking to tackle that challenge with the molecules that are coming forward from our platform.
Q: If there’s one piece of advice that you would give your younger self, what would that be?
I really come back to this whole idea about being a very authentic type of a person. If I could give myself advice, it would be to just be your true self at all times. I think I spent a good part of my early career trying to emulate a lot of phenomenal leaders that I had the opportunity to work with. And that’s great, but when you’re trying to be someone else, it takes away from you trying to be the best version of yourself. And I feel like I experienced that in my early years. So I think that now that I’ve started to focus on how I can be the best version of myself and be the true authentic Michelle Werner, I certainly wish that I knew that a little bit earlier and could start that journey at an earlier stage in my career.