"Raiders Of The Lost Codon:" Alltrna On Evolving "Ancient" tRNA Into Therapeutics

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

When I started researching tRNA for my interview with Alltrna’s CEO Michelle Werner, I didn’t expect to find myself immediately thinking about Indiana Jones. But the second I read about the company’s work on the “ancient” modality, tRNA, things started to get a little bit wild.
To be clear, at no point during my conversation with Werner did we have to stop to fend off thieves or miscreants trying to steal the company’s proprietary tRNA products. (Likewise, no snakes were present or harmed during the interview process.) But, as my conversation with Werner evolved from the basics of tRNA to the nuances of leading a young RNA biotech, I couldn’t stop making connections between Indiana Jones and the work we’re all doing to uncover the hidden mysteries of our molecules and their clinical significance. Much like archaeologists with historical relics, we’re striving to bring attention to ancient forms of biology and make them more relevant and known to patients around the world.
Short of putting a vial of our product in the Smithsonian, however, the question is: How do we best understand and underscore the significance of our products and build a successful business around an individual molecule? This question was the central focus of my conversation with Werner. But beyond focusing on what makes tRNA as legendary as Indiana Jones, we also drilled down into what it means operationally to be a front-runner when building a start-up biotech around a novel modality. Here, in part one of this two-part article, we identify how tRNA stands apart from other RNA modalities and gene therapies, as well as how this molecule’s unique “skill set” is guiding the company’s future clinical strategy.
tRNA In Brief: Unraveling The Mystery Behind The Molecule
It goes without saying: One does not simply happen upon a “hidden treasure” or relic without some significant research — or at least a treasure map. Likewise, mRNA doesn’t just magically turn into proteins. Just as we need someone skilled at decoding a treasure map and knowledgeably guiding us to the location of the treasure/relic itself, our mRNA also needs the ribosome and tRNA to read the mRNA’s codon sequence and to piece together the instructed protein, one amino acid at a time.
“The tRNA is what reads the mRNA’s code, understands which amino acid is needed, finds that corresponding amino acid in the surrounding cellular environment, and then transfers that amino acid to the growing protein chain,” Werner nicely summarized.
There are, of course, many resources in this world explaining the mechanics of tRNA’s biological function at much greater depth — including Alltrna’s website. I won’t be recreating those wheels here. However, we can’t ignore the basics of tRNA’s function entirely because, as Werner emphasized throughout our call, the molecule’s unique functionality is central to the product’s value proposition and informed how the company is carving out its initial clinical strategy.
In the still nascent RNA space in general, we’ve begun to ask a very important question: What does my RNA molecule offer this indication/patient population that other modalities cannot/do not? And for Werner and tRNA, it comes down to the fact that it is an “ancient” molecule. “tRNA’s function is a highly conserved part of the protein translation process,” she clarified.
Not only has tRNA always played a pivotal role in protein formation, but its function remains the same regardless of the cell type, the gene, the protein/size of the protein, and the location of a genetic mutation. While most therapeutic products in the ATMP and/or RNA space demand a gene- or protein-specific approach, tRNA’s biological function is “universal.” In turn, tRNA can be used across multiple diseases — a molecular/biological trait automatically setting it apart within the broader RNA/gene therapy space.
“Taking a gene- or protein-specific approach, as we do with mRNA, gene editing, and gene therapies, ultimately means it will take generations — or the life spans of many Indiana Joneses — to have relevant therapies for the thousands of genetic disorders in the world,” Werner added. “There are so many underserved patients because we’re often limited by this gene-by-gene or disease-by-disease therapeutic approach.”
Finding The Right Niche For tRNA
Though tRNA may have applicability across a broad swathe of diseases, I appreciated Werner’s acknowledgement that the universal functionality and the novelty of tRNA stand slightly at odds with each other when trying to build a business. While tRNA could be used in a variety of indications, it was important to identify where tRNA would shine — both in terms of proof-of-concept data, as well as in patients’ lives. As such, the company homed in on specific mutations known as nonsense mutations.
“Roughly 10 percent of patients suffer from a genetic disease that is caused by a faulty codon which instructs the tRNA to halt the production of the protein too early,” Werner explained. “You end up with a truncated version of the protein that is either non-functional or poorly functional.”
As she went on to explain, the company identifies patients with the same mutation across many different diseases as patients with “stop codon disease.” To treat “stop codon disease,” a therapeutic tRNA must be created with the ability to read through and ignore the premature termination codon to continue creating the full-length, wild-type protein.
While our conversation delved into a handful of operational challenges associated with the R&D of tRNAs (stay tuned for part 2…), I was struck predominantly by the marriage of tRNA’s function and the benefit/value it could inherently provide for the company’s future clinical trial design. It’s an unfortunate truth that many patients with rare diseases will be ineligible for specific trials and/or are part of a small population that will not garner therapeutic development attention. However, a molecule like tRNA that can be therapeutically applicable to different diseases (albeit caused by the same mutation) boasts a much more inclusive clinical opportunity for small patient populations — also known as a basket clinical trial.
As Werner concluded: “Patients across many different diseases that have the same mutation can be enrolled in a basket trial study, regardless of the size of the patient population. In fact, this is one of the biggest benefits of the basket trial; families whose loved ones may suffer from an ultra-rare disease and/or a mutation not currently represented by an ongoing clinical trial may be eligible for a basket trial because this type of trial does not require a patient population to be a certain size. This would provide something that many families do not have right now, which is the reassurance that something is being done and hopefully can continue to be done in the future with tRNA.”
My conversation with Werner didn’t stop here; in part 2, I’ll continue discussing Werner’s approach to leading Alltrna, homing in on two specific challenges she and her teams are facing in the process of establishing tRNA as a recognized and relevant modality.