Alltrna, a startup developing a new class of RNA-based drugs where a single therapy could potentially be reused across many different diseases, has received clearance to begin its first clinical trial, the company told
Endpoints News
in an exclusive interview.
The Cambridge, MA-based company’s therapies are based on transfer RNA, a natural molecule that helps translate the genetic code into proteins. Some genetic diseases are caused by mutations that interrupt that translation process, resulting in an incomplete protein. Alltrna has developed synthetic tRNA molecules that intercept those genetic typos and help the cell’s translation machinery finish making the protein.
The trial, which will begin soon in Australia, will be the first time a tRNA therapy has been tested in humans. Although the initial test will be in healthy volunteers, Alltrna is already planning a bigger basket trial that could pit the therapy against a dozen or more rare metabolic diseases. That study would enroll patients with the same kind of translation-terminating mutations that arise in different genes.
“Our approach with this tRNA is to be able to offer a therapy to all of those people, instead of just offering it to one disease at a time,” Alltrna chief medical officer Nerissa Kreher told Endpoints.
If tRNA therapies prove safe and effective, the mutation-specific but gene-agnostic medicines would represent a radically different way of treating genetic disease. The upcoming clinical tests will be a pivotal moment for the broader tRNA therapy field, which has faced several stumbles at a time when investor patience is wearing thin for new forms of genetic medicine.
At least two tRNA startups,
Theonys
and
hC Bioscience
, have shut down. Two more, ReCode Therapeutics and Shape Therapeutics, have shifted their focus to other kinds of RNA medicines. Tevard Biosciences, another leading tRNA startup with promising data in animal models of muscle and heart diseases, lost its partnership with Vertex Pharmaceuticals when the bigger drugmaker
pulled back on its genetic medicine research
last year.
Transfer RNAs, as tRNA molecules are formally called, are abundant and vital in every living organism. They are the assembly line workers of protein production that turn three letters of mRNA code — a unit that scientists call a codon — into a single protein building block, one after another, until the entire sequence is translated.
The protein-making machinery knows the job is done when it hits a special segment of code called a stop codon that normally sits at the end of the mRNA molecule. But genetic mutations can sometimes introduce stop codons in the middle of the message, resulting in truncated proteins that don’t work.
Alltrna is designing synthetic tRNA molecules that bind those premature stop codons and keep protein production going by supplying the amino acid building block that was supposed to be there. The company says roughly 10% of all genetic disease is caused by a premature stop codon.
“That’s 30 to 35 million people worldwide that are affected by what we view as stop codon disease,” Kreher said.
Researchers
first created
artificial tRNA molecules that could essentially overwrite premature stop codons in the early 1980s. But the idea didn’t gain traction in the biotech industry
until about five years ago
when several startups began attracting investment for the approach, including Alltrna.
Flagship Pioneering, the life science venture firm behind Moderna, quietly founded Alltrna in 2018 and launched the company with
$50 million
three years later. Alltrna raised another
$109 million
in 2023, making it the best-funded company focused solely on tRNA therapies.
Kreher said the 35-person company still has enough money to get through its Phase 1 trial.
Until now, a major focus for the company has been figuring out how to modify the tRNA sequence or decorate it with chemical modifications to make it more potent, selective and stable. At a conference in Boston earlier this month, the startup showed that highly modifying tRNA molecules can make them more stable but inhibit their activity.
“You can certainly over-engineer,” Alltrna’s chief scientific officer Dave Hava told Endpoints. “So finding this balance between stability and activity, and kind of an optimizing around those two parameters, is really what we have focused a lot of energy on.”
The tRNA therapies will be packaged in lipid nanoparticles and administered as an intravenous infusion. Kreher anticipates that the drug will likely require dosing “every several weeks” similar to enzyme replacement therapies approved for some rare metabolic diseases.
Alltrna recently got approval to begin a single ascending dose study in healthy volunteers. Kreher said the main goal of the Phase 1 study is to assess the safety and tolerability of different doses of the drug, dubbed AP003.
One of the biggest theoretical risks of a tRNA therapy is that the molecule could cause the protein-making machinery to blaze past the normal stop codons found at the end of every mRNA. That could potentially disrupt protein function or trigger an immune reaction.
“It’s the obvious question for this technology,” Hava said. “It’s been a big focus for us.”
So far, Alltrna and other groups developing tRNA therapies, including Tevard, say this unwanted readthrough of normal stop codons doesn’t seem to be a big problem in their preclinical experiments. Hava said this is partly because mRNA molecules often have multiple kinds of stop codons as a backup.
“If you were to read through that first stop, you’re almost certainly going to hit another stop,” Hava said. “If this is happening, you’re likely putting single digit amino acids onto the end of the protein. You’re not getting 100 amino acid or longer extensions.”
After its safety study, Alltrna will likely begin testing its drug in phenylketonuria, or PKU, a well-studied metabolic disease caused by mutations in an enzyme that breaks down phenylalanine. The approach appears to be working in preclinical studies.
In a mouse model of PKU caused by a premature stop codon, Alltrna’s tRNA therapy restored the vital enzyme to about 6% of its normal level, which was enough to reduce phenylalanine levels in the blood by nearly 80%, according to unpublished data the company shared with Endpoints.
Alltrna ultimately plans to launch a global Phase 2/3 trial — Kreher wouldn’t say when that might be — that includes PKU and other inherited metabolic conditions including several organic acidemias and as many as eight different urea cycle disorders.
“It opens up the opportunity to study multiple diseases at once,” Kreher said.
tRNA therapies won’t work for everyone with these conditions, since not every instance of the disease is caused by a premature stop codon and there’s more than one way a premature stop codon can arise. (Alltrna’s lead drug targets one of the most common forms in which a codon for the amino acid arginine is converted into the TGA stop codon.)
Despite those limitations, Kreher thinks the reusability of tRNA therapies will make them an economically viable path for ultra-rare diseases that “may not be feasible if we were just thinking about it on a disease-by-disease approach.”
