Issue link: https://www.e-digitaleditions.com/i/1534558
www.biopharminternational.com Next-Generation Biotherapeutics April 2025 BioPharm International ® 15 Transfer RNA Page Header_ Visser (Alltrna): tRNA is a unique component in the protein translation machinery. The whole body creates a lot of different proteins, in ever y cell, and tRNA is the one that translates the messenger RNA into a protein by inserting the correct amino acid. Genes encode proteins, and the mRNA serves as the transcript. T he t RNA binds to an m RNA codon— wh ich specif ies a n a m ino acid—a nd inser ts t hat a m i no acid i nto t he g row i ng pept ide cha i n. T he A l lt r n a fou nder s h ad seen so muc h prog ress i n t he m R NA a nd s i R NA [s m a l l i nte r f e r i n g R NA] therapeutic modalities, and recognized tRNA had un ique proper t ies. T hat led t hem [to] ask i ng t he question: could tRNA itself become a therapeutic? BioPharm: How are you leveraging it to create a new modalit y in RNA-based therapeutics? Visser (Alltrna): tRNA as a therapeutic is a novel concept—nobody ha s done t h is before, br i ng i ng tRNA into the clinical setting, and it really could allow for a disease-agnostic approach, because its action is not specific to one gene or one disease. A tRNA therapeutic can be engineered to fix specific mutations that affect protein translation. It's also unique in that it's not changing the genes or any of the coding because it's reading a problem in protein translation and allows the translation machiner y to overcome it in a reversible way. t RNAs are not changing the genetics or introducing genes. It's a reversible approach that can be applied, can be ti- trated, to leading to exactly what you need to have. A nd t h at br i ngs a not her adva nt age, wh ic h i s that because we are restoring the normal protein synthesis process with a tRNA, it's independent of the length of the protein. There are some proteins t hat a re so la rge t hat it's ha rd to pack age for ge- net ic med ici ne a nd t hat's not possible i n t he de- liver y mechanism. We can do that because we still have t he sma l l t R NA t hat ca n restore protein for any size protein. There are also diseases, k nown as "Goldilocks" diseases, where if you were to overexpress the pro- tei n above nat u ra l levels, you wou ld essent ia l ly create a new d i sea se cond it ion. One e x a mple i s Rett syndrome. tRNAs restore normal protein lev- els—they don't cause overexpression. That's really unique. I don't think there are any other medicines that can do that. So how do we consider tRNA's therapeutic poten- tial? We decided to focus first on nonsense muta- tions, also called premature termination codons. These prematurely stop protein translation, lead- ing to a tr uncated or missing protein. We are en- gineering tRNAs to read through a premature ter- mination codon and insert the correct amino acid, t hereby restoring f ul l-leng t h protein production and resolving disease. Stopping stop codon disease BioPharm: Let's talk about stop codon disease. What does this term mean, and how can tRNA assist in treating it as well as other rare liver diseases you are currently looking at? Visser (Alltrna): There are somewhere between 6000 to 10,000 different diseases driven by genetic mutations. Across all these diseases, approximately 10% of patients have a premature termination codon that causes their disease. That has led us to define these patients as having stop codon disease, where a nonsense mutation leads to a protein that's no lon- ger functional. And 10% of all rare disease patients with a genetic mutation is quite a lot—worldwide there are about 30 million patients that we believe have a nonsense mutation where their disease could then be classified under stop codon disease. So if we target nonsense mutations, then we have a huge potent ia l to accelerate t he t herapeut ic adva nces across all those patients—that's the beauty of this approach. We'll have to make sure it gets delivered to where it needs to go. So going to the liver, that is our first frontier. But essentially, the tRNA modality has potential to treat any disease that has a prema- ture stop codon. BioPharm: Alltrna announced its first develop- ment candidate in this field in December 2024. What is the current status of that candidate, and what is its expected timeline going forward? Visser (Alltrna): We have nominated our devel- opment candidate, and [in December 2024], we pre- sented [positive] data around the preclinical proof of concept. We have data in a stop codon disease mouse model for methylmalonic acidemia [MMA], which is a severe, inborn error of metabolism, and also in a stop codon disease mouse model for phenyl- Nobody has done this before, bringing tRNA into the clinical setting, and it really could allow for a disease- agnostic approach. — Sandra Visser, Alltrna