Flagship startup Alltrna raises $109M for tRNA therapies

Alltrna, a startup founded by Flagship Pioneering, has raised $109 million in Series B financing to develop a new class of genetic medicines based on transfer RNA molecules. It’s the largest round of funding yet for a company focused on ushering in an emerging class of genetic therapies that promises to override disease-causing mutations.

Although tRNA is well-known to biologists for its vital role in translating the messenger RNA code into proteins, the molecules have received little attention from biotech companies until relatively recently. Alltrna, hC Bioscience and Tevard Biosciences are among startups tinkering with tRNA.

In nature, tRNA pairs with a trio of letters in the mRNA code — a unit known as a codon — and hands off a corresponding amino acid to the cell’s protein building machinery. Genetic mutations called premature stop codons disrupt that process, resulting in a dysfunctional or completely missing protein.

Scientists hope to restore those proteins

By making synthetic tRNAs that pair with errant stop codons, scientists hope to slot in the missing amino acid and restore full proteins. And since there are only 19 possible ways a mutation can create a premature stop codon, Alltrna believes that a similar number of tRNA therapies could treat the thousands of rare and common diseases caused by such mutations, including certain forms of cystic fibrosis and epilepsy.

“We may have that potential to use a single medicine to treat hundreds, if not thousands, of different diseases,” Alltrna CEO Michelle Werner told Endpoints News. “It’s very unique compared to all other different approaches, such as gene therapy or gene editing.”

Alltrna collectively refers to those many conditions as “Stop Codon Disease.” They account for roughly 10% of all cases of genetic disease or about 30 million people worldwide. While it’s not an actual disease that a doctor would ever diagnose a patient with, Alltrna’s branding emphasizes the point that there’s a common cause shared by many of these conditions that could be addressed with similar, if not identical, therapies.

“Without the limitation of developing a new genetic medicine for each disease, Alltrna has the opportunity to scale a whole new field of programmable medicines,” Flagship founder and CEO Noubar Afeyan said in a press statement. Afeyan is also co-founder and chairperson of the board of Alltrna.

Werner said that her company, which has about 65 employees, will use the influx of cash to continue building its machine learning platform for designing tRNA medicines and move its first programs toward clinical studies. But she wouldn’t name specific genetic diseases Alltrna is focused on or give timelines for when she hopes to begin testing the first tRNA therapies in humans.

And with the exception of Flagship, which conceived the company in 2018 and launched it from stealth with $50 million in 2021, Alltrna is keeping the names of other investors who participated in its Series B round a secret. “There are a number of top-tier investors,” Werner said.

The first synthetic tRNA therapies

The company has presented at a couple of scientific conferences earlier this year, showing that an engineered tRNA delivered in a lipid nanoparticle could boost levels of a protein tenfold in a transgenic mouse model. But Alltrna didn’t divulge any specifics about its tRNA design, the gene it was targeting, or the disease it was treating.

While sporadic attempts testing tRNA molecules encoded in plasmids or viral vectors stretch back decades, Alltrna billed its recent data as the first time an “engineered” and “modified” tRNA therapy was used to restore proteins in an animal model.

“Before Alltrna, nobody had ever chemically synthesized a tRNA before,” Werner said. “This is the first time that’s ever been done. And the first time that it’s ever been shown to rescue that premature termination codon.”

The company decorates the nucleotides of its tRNA with chemical modifications to improve its properties and relies on machine learning to identify its optimal sequence. “Not all tRNAs are created equal,” Werner said. “We find that those tRNAs that are identified through this machine learning engine are far more successful than those found using a rational approach.”

Alltrna will be paying close attention to potential safety issues that could arise if tRNA therapies mistakenly cause machinery in cells to read past the normal stop codons that signal the end of a protein. But Werner notes that the “environment” around a premature stop codon and a regular one is “very different,” so the company believes it can design its therapy to selectively target the mutations.

“Certainly, this is a space that we’re monitoring very actively. We think it’s really important to be able to characterize this incredibly well,” Werner said. “And so far, we’re not seeing any indications that there is an off-target effect that we should be concerned about at this point in time.”

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gene editing
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