Long before we knew how they did it, human cells had refined the process for making proteins, the microscopic workers needed for pretty much everything our bodies do.
First, a special enzyme finds the instructions for a protein in our DNA. It then produces a piece of genetic information called messenger RNA, or mRNA, that acts as a template for another part of the cell, the ribosome, telling it what building blocks are required for the protein and what order they go in.
At the tail end of this operation are transfer RNAs, which, as the name suggests, carry and ultimately hand off the correct building blocks — known as amino acids — to the ribosome. But despite their crucial role, these molecules haven't attracted as much attention as other types of RNA. An article published not too long ago in the journal Cell Research claimed tRNA is "generally not on the mind of most research scientists, unless they meet it through chance encounter."
Theonie Anastassiadis, a principal at Flagship Pioneering, the startup incubator that founded mRNA specialist Moderna, noticed this lack of interest, too, when she began learning more about tRNA biology several years back. "I was so fascinated and blown away, and I questioned why no one else in this area was exploring it," she said.
The answer, according to Anastassiadis, was there were barely any tools to address some of the field's most basic scientific questions, like how to synthesize tRNAs or measure them. That need, along with what Flagship saw as an opportunity to create new medicines, led to the 2018 formation of a drug company focused exclusively on tRNA.
Now named Alltrna, the company officially launched Tuesday with an initial commitment of $50 million from Flagship. The firm's origination partner, Lovisa Afzelius, is serving as Alltrna's founding CEO, while Anastassiadis, in addition to being a co-founder, is taking on the role of chief innovation officer.
"Transfer RNA is the last critical step of protein translation," Afzelius said. "Without tRNA, there is no protein being made. And yet, it has been completely overlooked."
The launch gives Alltrna a chance to put tRNA in the spotlight, as well as the technology it's been working on for the past few years. According to Afzelius, the platform can engineer tRNA molecules so they spot erroneous genetic code and replace it with the correct amino acid, thereby restoring protein production and treating disease.
Alltrna executives aren't yet disclosing what diseases the company will go after, though they note how different genetic disorders — from the ultra rare to the more common — are of interest.
Another important aspect of tRNA molecules, according to Anastassiadis, is that they can break apart into new units with functions beyond translating protein code. Research indicates those roles can range from affecting gene expression to the transcription of retroviruses.
"When you start really thinking about that whole field, you realize you can not only design novel [ways of programming] tRNA medicines, but you can also leverage this completely understudied biology," Anastassiadis said.
Like other Flagship companies, Alltrna has set up a wide assortment of preclinical programs to allow it to test various payloads, delivery methods and tissue targets. While Afzelius declined to provide specifics, she said that in the "not too distant future," Alltrna could reach the stage where it asks regulators for permission to begin human testing.
Also like other Flagship companies, Alltrna has big ambitions, claiming each tRNA medicine it develops could have applications across many diseases.
Yet, successfully advancing a drug for more than a small number of related diseases is a rarity in the pharmaceutical industry, even for the most prolific developers. Proving a new technology is harder still, often requiring many years of work to refine how it can be safely used in the body.
Flagship, though, appears confident in its latest investment. Afzelius said the firm is "extremely committed" to helping establish a tRNA platform, and that Alltrna "will have access to the capital we need in order to do so." Flagship CEO and Moderna chairman Noubar Afeyan is also one of Alltrna's co-founders.
Alltrna follows in the footsteps of two other RNA startups from Flagship. The more widely known of them, Moderna, has become a household name and one of the most valuable biotech companies since developing a highly effective coronavirus vaccine. The other, Laronde, is researching so-called endless RNA, and recently raised more than $440 million in funding.
While RNA has come into focus for both drugmakers as well as investors, the field has taken decades to mature. Moderna's road to coronavirus vaccine success, for instance, was lengthy and not without its share of setbacks and skepticism. Just last week even, the company revealed that it won't be advancing an antibody treatment viewed by some as important to instilling confidence in its work outside of vaccines.
Still, Afzelius sees Flagship's experiences with Moderna and Laronde as a major advantage for her company. "We can leverage that depth of RNA knowledge from within the ecosystem," she said.
