Transfer RNAs (tRNAs) are molecules that help cells build proteins. Think of them as translators between the genetic code and the amino acids that make up proteins.
Each tRNA carries a specific amino acid and recognizes a matching three-letter sequence, called a codon, on a messenger RNA (mRNA) molecule. As the cell reads the mRNA, tRNAs bring in the correct amino acids one by one, forming a chain that folds into a working protein. In some genetic diseases, such as Duchenne muscular dystrophy (DMD), a “nonsense” mutation introduces a premature stop signal in the mRNA, causing the protein to be cut short and lose its function.
Tevard Biosciences has developed special engineered tRNAs, called suppressor tRNAs, that can read through the faulty stop signals and insert the correct amino acid, enabling the cell to make full-length, functional proteins again. In their studies, suppressor tRNA treatments restored up to 70 percent of normal dystrophin levels in models of Duchenne muscular dystrophy. We talk to CSO Elisabeth Gardiner to find out more.
How could suppressor tRNAs work together with other RNA therapies, base editing, or RNA repair to treat genetic diseases with nonsense mutations?
Suppressor tRNAs can complement other RNA technologies. For example, in combination with mRNA therapeutics, the co-delivery of suppressor tRNAs can enable readthrough of premature termination codons (PTCs) in mRNA payloads, restoring full-length protein expression. In combination with base editing strategies, they can serve as a stopgap or adjunct to base editors that correct nonsense mutations at the DNA level, especially when editing efficiency is low. In combination with RNA repair/editing, Adenosine Deaminases Acting on RNA (ADAR)-based systems may be able to transiently correct mRNA transcripts, while suppressor tRNAs can ensure translation continuity and the production of full-length proteins.
As monotherapies, suppressor tRNA strategies could offer robust rescue of full-length protein. In our own preclinical studies, we’ve observed on average 70 percent restoration of wild-type dystrophin protein in DMD, as well as compelling restoration of full-length titin protein in dilated cardiomyopathy caused by titin truncations (DCM-TTNtv). This shows how suppressor tRNA technology has the potential to provide potent and durable efficacy for diseases caused by nonsense mutations.
Suppressor tRNAs therapies can be used as an effective monotherapeutic approach, but they can straddle the intersection of mRNA therapeutics, base editing, and RNA repair, and may offer a multi-functional approach to nonsense mutation diseases.
How do you see the evolution of engineered tRNAs reflecting broader trends in rational RNA design?
Engineered tRNAs exemplify the shift toward precision RNA therapeutics, where interventions are tailored to specific codons and cellular contexts. This reflects a broader trend in rational RNA design: moving from generalized modulation to programmable, codon-level control. Technologies like suppressor tRNAs and genetic code expansion leverage orthogonal tRNA-synthetase pairs to suppress premature stop codons or incorporate non-canonical amino acids, enabling functional rescue of proteins with high specificity. This codon-centric approach is foundational for treating diseases caused by nonsense mutations and aligns with the field’s push toward modular, scalable RNA platforms.
What does the data say about expectations in the RNA field?
The RNA therapeutics field is maturing rapidly. Over 5,500 RNA drugs and 2,500 trials are active, with a 13 percent surge in pipeline assets in just the past six months. Beyond mRNA, modalities like suppressor tRNAs, siRNA, antisense oligonucleotides (ASOs), and circular RNA are gaining traction. Cancer therapeutics and rare diseases remain dominant in the RNA therapeutics space, but there is growing interest in neurology and cardiology.
Additionally, manufacturing competency is evolving with the interest in RNA therapies. Agile, small-scale GMP production is emerging to support personalized therapies, reflecting a shift from pandemic-scale vaccine production to precision medicine. These trends show that RNA therapeutics are transitioning from experimental to mainstream, with expectations now centered on scalability, precision, and commercial viability.
How does the field of RNA therapeutics need to adapt when tackling large, multidomain proteins versus smaller enzymes or receptors?
Large, multidomain proteins pose unique challenges in terms of size, complexity and the need for repeat dosing. Specifically for delivery, large, complicated proteins may require multi-exon targeting or full-length mRNA delivery, demanding more robust vectors or lipid nanoparticles. With regard to complexity, RNA editors must navigate complex folding and domain interactions, which can reduce accessibility. If the goal is treatment durability, sustained expression may be hard to achieve with standard therapies or non-viral delivery mechanisms, especially in tissues with high turnover. Focusing on diseases with low cellular turnover may be required to successful disease remediation.
The aim of tRNAs as therapeutics is to address these issues as they take up limited genetic real estate and allow the cell to make proteins naturally – known as “native translational machinery”. In my view, the field of genetic therapies will benefit from utilizing tRNA therapeutics as part of the gene therapy toolbox, but the field still needs to develop scalable delivery systems and multiplexed editing strategies to address the complexity of larger targets.
How will durability and redosing challenges shape the next wave of innovation in RNA and gene-based therapies?
Durability and redosing are the pivotal challenges shaping the process of therapeutic innovation in the genetic disease space. Patients are expecting therapies to deliver long-lasting, hopefully curative effects.
Innovations in delivery platforms such as tissue-targeted AAVs or GalNAc conjugates may help to extend the therapeutic impact. One issue is that immune responses to proteins that are delivered as ex vivo-produced proteins may promote immunogenicity. In addition, viral vectors like AAVs do not currently permit patient redosing, and there is currently no standardized guidance for designing clinical trials to explore re-dosing. This is prompting research into immune-modifying techniques. The positive aspect of these challenges is that the hurdles are accelerating the development of non-viral delivery methods, RNA editing technologies, and modular payloads. Solving durability challenges and being able to redose is not just a technical hurdle, but a strategic imperative for patients that will define the next generation of gene therapies.
One promising approach involves the use of imlifidase, an enzyme developed by Hansa Biopharma. Imlifidase cleaves IgG antibodies, including those targeting AAV vectors, possibly eliminating the major barrier to gene therapy eligibility and redosing. Although early, an initial human trial suggests enzyme-based immune modulation could expand access to AAV-based gene therapy and potentially enable safe redosing.
Newsletters
Receive the latest pharmaceutical news, personalities, education, and career development – weekly to your inbox.
