Genetic medicine has made huge progress over the past two decades. Gene therapy, gene editing, and mRNA treatments are now approved for a growing number of conditions. These approaches focus on fixing or replacing a single faulty gene. This has brought real benefits to some patients, but it has also created a fragmented system, where thousands of rare diseases each need their own separate therapy.
Transfer RNA, or tRNA, therapeutics take a different approach; instead of targeting DNA, they act later in the process, when cells make proteins. This means that one therapy could potentially work across many diseases that share the same type of genetic error.
One company working in this area is Alltrna. Their chief scientific officer, Dr. David Hava, spoke to Technology Networks about how this approach could change the way genetic diseases are treated.
To understand why this matters, this article looks at how genetic medicines have traditionally worked, where they fall short, and how tRNA therapeutics aim to offer an alternative.
Why translation is emerging as a therapeutic target
Most genetic medicines focus on genes themselves; for example, gene therapy delivers a working copy of a faulty gene, gene editing tools attempt to correct mutations, and mRNA therapies provide instructions to make missing proteins. Each therapy is typically designed for one gene and one disease.
“Most genetic medicines start with the gene, either fixing it, replacing it, or changing how much RNA is made. These medicines usually are targeted at a single gene and are applicable to a single disease, resulting in a ‘one drug-one disease’ paradigm,” explained Hava.
Developing a new therapy in this way takes years and costs a lot of money. For rare diseases with small patient populations, this makes treatment development difficult—leaving many patients without options.
Genes carry instructions stored in DNA. These instructions are copied into RNA, and the cell then reads RNA to build proteins, which carry out most biological functions. tRNA helps assemble proteins by bringing the right building blocks into place.
“In many diseases, the gene and RNA are present, but the protein never gets made correctly because translation breaks down,” said Hava.
This means the problem is not always the gene itself, but the process that reads it.
“By acting at the ribosome (the translation machinery), engineered tRNAs address that failure directly, without changing the DNA,” he added.
This idea has become possible because of recent progress in RNA science. Researchers can now design and deliver RNA molecules more reliably.
“Advances in RNA chemistry, delivery, and analytical methods made it possible to design engineered tRNAs that function predictably in cells and can be evaluated with the same rigor as other drug modalities,” Hava said.
“Once that became possible, we could ask a different kind of question: instead of targeting individual genes, could we correct a shared failure in translation itself? Because every protein in every cell depends on tRNAs to be made, and they work independently of gene size, mutation location, or expression level. That shift, from gene-level intervention to addressing a common translational error, is what led us to view tRNA as the foundation of a scalable therapeutic platform,” explained Hava.
Fixing protein production across diseases
This shift is now moving from theory into drug development, and Alltrna is working to translate this idea into treatments.
Alltrna is currently focusing on nonsense mutations, which introduce a stop signal too early during protein production. As a result, the protein is cut short and cannot function.
“Nonsense mutations create a very clear problem: translation stops too early, resulting in an incomplete or missing protein. There is no natural tRNA that can read a premature stop codon, so translation stops when the machinery reaches a nonsense mutation,” said Hava.
These mutations are found in many inherited diseases and are responsible for ~10–15% of inherited genetic diseases, making them an attractive initial target for this approach.
Alltrna’s strategy is to design engineered tRNAs that allow the cell to continue reading past the faulty stop signal.
“Engineered suppressor tRNAs are designed to fill that gap by inserting the correct amino acid, allowing translation to continue and restoring full-length protein synthesis,” Hava explained.
Since this approach targets the type of mutation rather than a specific gene, its reach could be wider.
“This offers the potential for a tRNA medicine to act at different genes and across different diseases where there is a common shared mutation, enabling us to think about the application of one drug across many diseases,” he said.
“Alltrna’s engineered tRNA therapeutics are delivered as synthetic oligonucleotides, which means we can use existing systems that have been used to deliver other RNA-based medicines, like lipid nanoparticles,” said Hava.
“Additionally, given their small size, tRNA therapies can also be delivered using adeno-associated viruses. Unlike gene therapy, there’s no permanent change to the genome, and unlike mRNA, we’re not introducing a new transcript that needs to be expressed at high levels,” he added. “From a development standpoint, that gives us flexibility, including the ability to dose, redose, and optimize delivery as we expand into new tissues and indications.”
As tRNA therapies do not permanently alter DNA, treatment can be adjusted or stopped if needed.
However, precision is essential; the therapy must fix faulty stop signals without interfering with normal ones.
“The challenge is making sure you fix the error without disturbing normal biology,” Hava said. “Premature stop codons and natural stop codons sit in very different contexts, and the cell has strong safeguards around normal termination with house-keeping mechanisms that make read-through at normal termination codons more difficult than at premature termination codons.”
“Our job is to design tRNAs that are active at premature termination codons, but do not substantially alter normal termination readthrough. We test this extensively, looking not just at protein readthrough, but at overall translational fidelity and cellular responses, to make sure normal termination remains intact while the premature stop is corrected,” he explained.
The future of platform-scale genetic medicines
While nonsense mutations are the starting point, the broader goal for tRNA therapeutics extends further.
“It changes the unit of focus from the disease name to the underlying mechanism. The same translational error can show up across many different genes and conditions, which means a single engineered tRNA could potentially help multiple patient populations,” said Hava.
This could also change how clinical trials are run, opening the door “to more efficient clinical development, including basket-style approaches in rare disease. It also creates a path to reach patients who are often left out of drug development opportunities because traditional, ‘one gene, one drug’ approaches are not accessible,” he added.
Beyond nonsense mutations, other errors in protein production may also be addressed.
“Translation can fail in several ways, not just through premature stop codons. Frameshift mutations, codon misinterpretation, and stress-related translational dysregulation all disrupt how proteins are made,” Hava explained.
These areas are still being studied, but they point to wider potential.
“While nonsense mutations are our initial focus because the biology is clear and the therapeutic goal is well defined, the broader platform is built around understanding translational errors more generally. As that biology becomes better understood, engineered tRNAs could be applied to additional classes of translational defects in a controlled, disease-relevant way,” he said.
This means tRNA therapeutics could develop into platform technologies. Instead of creating thousands of separate treatments, researchers could design smaller sets of therapies that apply across many conditions.
The next step for RNA-based therapies
tRNA therapeutics represent a different way of thinking about genetic medicine.
However, the approach is still under development, and questions remain about its long-term safety, delivery, and effectiveness in patients—tRNA therapeutics will need to show a clear clinical benefit.
If successful, however, they could make treatment development more efficient and expand access to patients who currently have few options.