In a recent episode of The Genetics Podcast, Patrick sat down with Michelle Werner, CEO of Alltrna and CEO Partner at Flagship Pioneering. If you’ve been following the podcast, you might remember Michelle from Episode 139, where she introduced the potential of tRNA-based therapies for rare genetic diseases. A lot has happened since then. Now, with exciting preclinical data in hand, Michelle shared Alltrna’s progress, the challenges of pioneering a new therapeutic modality, and how basket trial design could change the way we approach rare disease treatment.
A new approach to treating rare diseases
Alltrna is creating a new class of genetic medicines using transfer RNA (tRNA) to address a broad range of conditions caused by nonsense mutations (also known as premature termination codons). These mutations disrupt protein synthesis, leading to truncated, nonfunctional proteins that drive disease.
Approximately 10% of all genetic diagnoses stem from nonsense mutations, which can cause what is known as stop codon disease. Alltrna is engineering tRNAs to override these premature stop signals, allowing cells to produce full-length, functional proteins. Remarkably, out of the 19 possible nonsense mutations, just two account for about half of all cases. This means a single tRNA therapy could potentially treat many different diseases at once.
By focusing on common genetic mutations instead of tackling one disease at a time, Alltrna’s tRNA-based therapies have the potential to reach far more rare disease patients. This approach could make treatments more accessible and efficient in a field where drug development has often been slow and limited to just a handful of conditions.
Preclinical proof of concept
Since Michelle’s last podcast appearance, Alltrna has achieved a major milestone by demonstrating preclinical proof of concept in two rare disease models—methylmalonic acidemia (MMA) and phenylketonuria (PKU):
- In the MMA model, Alltrna’s engineered tRNA restored nearly 50% of normal protein levels—a significant achievement considering that clinicians believe just 1-2% restoration could meaningfully impact disease progression.
- In the PKU model, protein restoration led to a 76% reduction in phenylalanine levels, a key biomarker for disease severity.
These results provide compelling evidence that tRNA-based therapy can successfully restore protein function in vivo, strengthening the case for advancing to clinical trials.
Basket trials for rare diseases
A major challenge in rare disease research is the difficulty of running large-scale clinical trials for small patient populations. Alltrna is tackling this problem with a basket trial approach, which has been widely used in oncology but is relatively new in rare disease research.
In a basket trial, patients with different diseases but a shared genetic mutation are grouped together and treated with the same therapy. This allows researchers to assess efficacy across multiple diseases simultaneously, speeding up development timelines and expanding access to treatments.
Alltrna’s first basket trial will focus on diseases that share similar biology and have clear biomarkers to track progress, making sure the results are both meaningful and reliable. Over time, this approach could be expanded to include even more diseases, helping to bring treatments to patients faster and more efficiently.
Overcoming the challenges of tRNA therapies
As with any new treatment, there are challenges to overcome. One of the biggest hurdles in genetic medicine is delivery—ensuring that the therapy reaches the right cells in the body. Alltrna has initially focused on lipid nanoparticle (LNP) delivery, a well-established method proven in millions of people through mRNA vaccines.
However, tRNA has the potential to be adapted to other delivery platforms, such as AAV gene therapy or novel conjugation strategies that could target tissues beyond the liver. As delivery technologies continue to evolve, the versatility of tRNA-based therapy could expand to treat conditions affecting the brain, muscles, and other critical organs.
Regulatory pathways and the future of rare disease treatment
Regulatory agencies are increasingly open to innovative trial designs and broader treatment approaches, especially for rare diseases where traditional clinical development can be slow and fragmented. In the podcast, Michelle discusses the importance of working closely with regulators to establish clear pathways for tRNA therapeutics, balancing scientific rigor with the urgent need for new treatments.
Alltrna is preparing for its first clinical trials and will engage with regulatory bodies to ensure a smooth transition from preclinical to human studies. The company’s goal is not just to validate tRNA as a therapeutic approach but also to pave the way for future applications beyond nonsense mutations, potentially addressing other types of genetic errors such as missense and frameshift mutations.
Moving forward: Reasons to believe
Throughout the conversation, Michelle talks about the importance of data-driven decision-making and a framework she calls "reasons to believe"—a systematic approach to evaluating each step in the development process. By continually asking, “Do we have a reason to believe this will work?” Alltrna ensures its progress is grounded in solid scientific evidence while maintaining the urgency needed to deliver new therapies to patients.
As Alltrna advances its research, the promise of tRNA therapy is becoming increasingly tangible. If successful, this approach could fundamentally reshape how we treat rare diseases, offering a scalable and efficient alternative to the one-disease-at-a-time model that has long dominated genetic medicine.
Listen now:
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