Trace Neuroscience: Eric Green
“Organizations that have a clear, shared purpose are powerful”
Precision separates expert and novice. The rich vibrato of the cellist, practiced plié of the ballerina or smooth turn of an F1 driver are complex movements that fall flat if off by a second or centimeter. Yet all of us rely on equally precise movements for our daily survival—the vibrations of our vocal cords that allow us to speak, the fine contractions of skeletal muscle that permit us to button a shirt, the descent of the diaphragm that draws air into our lungs. If any of these movements are slightly disrupted, disaster ensues.
Precision separates health from disease. Each second, thousands of tiny vesicles are released from a given motor neuron: allowing them to communicate with other neurons and muscle fibers. This complex coordination between nerve and muscle depends on the fidelity of synapses—the physical touch points neurons make with each other, and with innervated muscles. Synaptic dysfunction is an early hallmark of many neurodegenerative diseases. In amyotrophic lateral sclerosis (ALS), upper and lower motor neurons are damaged, leading to aberrant communication with muscle fibers: “altered synaptic transmission is at the heart of ALS pathology,” describes Dr. Eric Green, co-founder and CEO of Trace Neuroscience, “early in the disease you see dysfunction in the synapse that precedes loss of the motor neuron [cell body].” Without precise communication between nerve and muscle, these patients gradually lose the ability to move, speak, swallow and breathe.
But what drives early synaptic dysfunction in disorders like ALS? “In 2022 there were two breakthrough papers from the labs of Aaron Gitler [Stanford] and Pietro Fratta [UCL], which linked TDP-43 pathology to the loss of UNC13A” says Green. TDP-43 is a nuclear protein that contributes to RNA processing. When abnormal aggregates of TDP-43 trap this protein in the cytosol, it is unable to perform its normal role in (nuclear) RNA splicing. Ninety seven percent of ALS patients have TDP-43 inclusions in their motor neurons, effectively leaving these neurons “deficient” in nuclear TDP-43. Gitler and Fratta showed that loss of nuclear TDP-43 impacts downstream splicing of UNC13A—a protein that primes synaptic vesicles for release. “UNC13A disruption blocks a key step in the chain of events in nerve and muscle function,” states Green, “it is just one node in a complex pathology…but genetic evidence highlights its importance.” Mutations that impair UNC13A splicing are independently associated with increased risk and faster progression in ALS and FTD, strengthening the notion that UNC13A deficiency is central to pathology.
Trace Neuroscience is developing an anti-sense oligonucleotide (ASO) that aims to correct aberrant UNC13A splicing—by restoring functional UNC13A to motor neurons they hope to slow disease progression. “My career [in biotech] has focused on developing therapies that leverage human genetics,” says Green. A cardiologist by training, he cut his teeth at MyoKardia before co-founding Maze Therapeutics and joining as their CSO: “the genetic platform at Maze laid the groundwork for the approach we took when founding Trace,” describes Green.
Precision separates expert from novice, health from disease, and success from failure in drug development. Green and his team hope that by developing a targeted therapy—correcting just a single mis-spliced RNA—they can restore synaptic precision to a dysfunctional nervous system. “It is impossible not to feel bonded to patients suffering from ALS,” emphasizes Green, “though there are promising genetic therapies [e.g., Tofersen] available for a small subset…the majority are in need of a breakthrough.” As Trace pushes their work into humans early next year, Green hopes to provide precisely that.
Below is an interview with Dr. Eric Green co-founder and CEO of Trace Neuroscience from May 2025:
1. What initially got you interested in science and medicine? Who were some early mentors that pushed you in this direction?
My father was an oncologist, who retired just last year. There were always medical textbooks in our house, and I was always curious—especially about the molecular and genetic contributions to disease. For example, when I was in 6th grade I did a project on schizophrenia and its causes. I remember feeling like there was so much mystery in this area [neuroscience]. What is going on in the brain to cause this disease? Unlike a broken bone, there is no clear cause or solution. These types of problems have always appealed to me.
As a college student, I fell in love with chemistry and started working in Greg Verdine’s group at Harvard. I came to really appreciate curiosity-based discovery and considered myself more of a budding scientist—however, I was always drawn to practical applications to health and disease. So, given that I loved science but wanted to impact human health, I decided to pursue MD-PhD training at Stanford.
2. You started iLabs (acquired by Agilent) while still an MD-PhD student. What did this early experience teach you about innovation?
I never considered starting a company while an undergrad at Harvard. At the time [my advisor] Greg Verdine was starting some companies, but it was not common practice—and still somewhat “taboo” to do so as an academic. Then I went to Stanford [MD-PhD program] in the 2000s—this was in the early days of Google, and it was a totally different environment than Boston. A lot of my friends during grad school were in the computer science or electrical engineering departments. They aspired to work in Silicon Valley and start companies. Being at Stanford just opened my mind to entrepreneurship.
My college roommate and I co-founded iLabs (together with a few other classmates)—he had been a consultant at McKinsey, and we had been discussing inefficiency in scientific research. We realized that while the operating budgets were large for these research organizations, the systems that scheduled and managed research were primitive. We founded iLabs, and the company went through a number of pivots. Ultimately, we focused on making scheduling software for core facilities—where we felt there was the most opportunity. I loved the process of starting a company, and how interdisciplinary it was. The venture ended up being quite successful and got a lot of traction amongst research facilities. This experience, and being at Stanford and Silicon Valley, made me eager to work on another startup in the future. However, I felt that what I really wanted to do [as an entrepreneur] was contribute my deep knowledge in science and medicine to building companies. I finished at Stanford and started as a resident at Brigham and Women’s Hospital, with the intent of establishing myself in academia and then moving into biotech.
3. After finishing your medical training, how did you come to be involved with MyoKardia?
As a cardiology fellow, one of the questions on my mind was how we could leverage the emerging genetics of heart failure to make new therapies for patients. Unlike some genetic diseases where you could draw a straight line between the genetic defect and clinical presentation, in heart failure it was more complex. Often families could have the same mutation but very different disease manifestations. In thinking about this issue, I learned about the work going on at Third Rock Ventures (TRV)—this was in 2012, so just a couple of years after the firm was founded. TRV was taking an unconventional approach in creating and financing companies, which is now more common today. Their mission was to build companies that really took advantage of an emerging area of basic science that could help patients. I got to know the group at TRV, and they happened to be creating MyoKardia at the time. It felt like a great fit, because I could leverage my clinical knowledge [in cardiology] and deep interest in human genetics.
[What initially drew you to TRV?]
I had done some work in venture previously and felt it to be interesting and energizing. However, I did not want to be a traditional investor—I wanted to help build and operate companies as an entrepreneur. At the time (2012) Third Rock was itself a startup, so I felt there was a ton of energy to be creative in building impactful companies. The culture was terrific, and I was learning a lot from experienced entrepreneurs and investors. It was exactly what I wanted, and set out to find, when came to Boston.
[Mavacamten was approved, and MyoKardia was acquired for $13B – a win for patients and investors. What were some of the key lessons about biotech you learned from this experience?]
There are some general lessons from MyoKardia, many of which really came from Charles Homcy. Charles is a cardiologist, partner at Third Rock and one of my most important mentors in biotech. He really was the guiding force behind MyoKardia. Some general lessons I learned were to really look to genetics to guide drug development, which is an orientation I have taken to Maze and now Trace. Advances in sequencing and genomic profiling have made this easier over time and enabled a lot our current work [at Trace]. Another lesson is to remain close to patients. At MyoKardia all of us, even those of us who were not clinicians, got to spend time with people who had hypertrophic cardiomyopathy. Especially in genetic diseases, it is important to have a strong connection to patient families. This is another lesson I have brought with me to Trace: every person who works here has met somebody with ALS. Every one of our investors has met somebody with ALS. The patient experience really helps to keep everybody focused on our one shared goal. Organizations that have a strong shared purpose are powerful and can accomplish great things—this was a lesson I learned from Mark Levin, one of the founders at Third Rock.
4. What was the founding vision of Trace, and how did your experiences at MyoKardia and Maze influence this vision?
The experience at MyoKardia taught me that rooting drug discovery in human genetics is a powerful approach. In 2017 we were starting to see a huge explosion in the availability of genetic data and biobanks, so it was a moment where it was possible to think about a platform to generalize these discoveries. That was the core problem statement that we had when I went back to Third Rock to start Maze. We spent the next several years building an engine to characterize genetic insights and develop precision drugs based on these learnings. We wanted to identify several areas to focus our efforts, which were mature enough in terms of the science and could impact patients significantly. ALS was an area we identified early on at Maze, and we started working with Aaron Gitler at Stanford, whose lab was focused on this disease. Over my five years at Maze, we had success in several rare diseases, which validated our approach—Pompe and genetic [APOL1] kidney disease for example. In 2020, working together with Aaron Gitler we made an important scientific breakthrough that unlocked UNC13A as a therapeutic target for ALS. After some exploratory work, we felt we could move on this target quickly and it could have a huge impact. By this point I had developed a strong connection to the ALS patient community and felt a calling to do everything I could to bring these patients and families a meaningful treatment. As I reflected on how best to do this, it became clear to me that we needed the specialized expertise, resources and focus of a dedicated company.
5. What do we know about the biology of UNC13A?
The discovery we made together with the Gitler and Fratta labs was that UNC13A, which is an essential gene for synaptic transmission, is lost in nearly everyone with ALS by a very specific mechanism. When TDP-43 accumulates in the cytosol (an early hallmark of disease), UNC13A RNA becomes improperly spliced leading to its degradation and loss of the protein. We already knew from human genetics that variants in UNC13A increased the risk for developing ALS and accelerated disease progression. However, until these discoveries we didn’t understand how this was working and so couldn’t effectively design a medicine. This was one of the rare basic discoveries that both sheds light on disease mechanisms and immediately points the way to a therapeutic approach. We hypothesized that if we could find a way to prevent improper splicing and restore UNC13A, we could preserve synaptic transmission and motor function. Based on previous groundbreaking work in spinal muscular atrophy (SMA) with nusinersen, we thought that an ASO could be developed as a medicine that would bind the UNC13A RNA and ensure its correct splicing.
I vividly remember discussing this discovery with Aaron [Gitler] in 2020, and we both came back to the point that the combination of human genetics and mechanistic understanding gave us enormous conviction—UNC13A mutations increase propensity for mis-splicing of this molecule and also lead to more severe disease. Thus, we felt that out of the hundreds of mis-spliced genes in ALS, restoring this target could substantially alter disease progression. Over time, we have reinforced that confidence by showing that correcting UNC13A mis-splicing in cellular models of ALS is sufficient to rescue defects in synaptic transmission.
As a cardiologist, I see some parallels between ALS and diseases like heart failure—indications where we have multiple effective drugs that impact different nodes of disease biology. We think UNC13A and synaptic function is one very important pathway in this disease, and we are trying to correct it with an ASO. We have confidence based on human genetics that it will have an outsized impact on disease progression. I hope that one day it can be part of a toolkit of complementary mechanisms for treating this disease.
6. What are the main challenges to developing an ASO in neurology? What has Trace learned from past failures in ALS and other conditions?
There are a lot of issues, including delivery of drugs to the right cells, clinical trial design and biomarkers that are particularly challenging in neurology. At Trace we have worked hard to build this expertise in house and through our network of advisers, as we develop an UNC13A ASO. We have learned a lot from the experience at Biogen with Nusinersen [SMA ASO] and Tofersen [SOD1 ASO], which is tremendously helpful. Finding good biomarkers of target engagement and early clinical benefit are important, and we are investing in developing some of these ourselves. We are fortunate that in ALS we are a little further along in terms of biomarkers than a space like psychiatry, for example. Ultimately at Trace, what we have learned from some of the successes in neurology is the importance of having the triad of genetic target validation, clear mechanistic understanding and a specific modality [ASO] to hit our target. When those pieces are in place, you have the greatest chance of being successful. The number of programs across neurology that have these three components is not that large.
[How do you measure UNC13A target engagement?]
There were no preexisting assays for doing that. We are having some good initial success at building assays, but it's been a tour de force trying to get these to work from cerebrospinal fluid (CSF) samples. We have to build extremely sensitive assays, since there is not much UNC13A normally present in the CSF.
7. What are some of the milestones and catalysts you feel will be important for Trace over the next year
The moment we’ve circled on our calendar from day one is when we will enter human trials. We continue to be on track to do this in the early part of next year [2026]. Right now, this occupies the vast majority of our attention.
8. What are some approved (or late stage) drugs in neurology, or companies that help provide Trace with a roadmap for success?
In many cases, the nervous system is a harder place to go than other areas. We are now starting to see good success with ASOs in neurology: in ALS and other neuromuscular disorders like SMA. In terms of other programs, I am excited about what Stoke Therapeutics is doing for Dravet Syndrome—applying targeted ASOs to correct a mutation [SCN1A] that causes a form of pediatric epilepsy. As I mentioned before, they have a triad of genetic validation, mechanistic understanding and the correct modality. We are hoping to be part of this lineage at Trace, and we believe that we have the correct target and molecule to make a difference for patients.
9. On a more macro level how do you keep your team motivated given the current environment?
There is no doubt that it's a very challenging moment for biotech…a moment that is lasting quite a while now. I think you must be a bit of an irrational optimist in this business, given everything we know about the rates of failure across the industry. But I do continue to have an abiding faith there are a lot of areas of medicine where there are important unmet needs. ALS is only one example. If drug development is successful for these conditions, there are going to be viable businesses. Private and public markets will reflect that [eventually]. I think the environment will improve and we will see more companies rewarded for pursuing novel biology with a laser focus on patients’ unmet need. At Trace, I just try to always remind our team of the mission and the patients we serve.
10. Any advice for trainees hoping to have a career in biotech or drug development? What is a piece of advice that you wish you had received earlier in your career?
My dad was a practicing oncologist for his entire career. My mom was a teacher for 40 years. Growing up, I thought this is what a “profession” or career looked like. Now, I think there are multiple ways to go about having a career: one with multiple chapters, especially in biotech. Some are in academia for decades before entering industry, and others go into biotech even earlier than I did. I think there is a lot of opportunity with new paths opening all the time due to advances in science and evolution in company creation models. My main advice is to be flexible and open to that serendipity. Be bold, have confidence in yourself and take those chances when they present themselves.