With a new startup, ARCH and Takeda wade into growing search for a Swiss Army knife RNA drug
ARCH and Takeda are stepping — if not quite leaping — into one of the hottest new areas in RNA drug development: tRNA.
On Wednesday the prominent VC firm and the Japanese pharma, along with tech-oriented 8VC, announced a $24 million investment in hC Bioscience, a new startup that will try to use this once-overlooked corner of genetic machinery to develop treatments for rare diseases and cancer.
The promise of tRNA, or transfer RNA, rests in its Swiss Army knife versatility. Unlike with other forms of genetic medicine, such as mRNA or gene therapy, where each candidate has to be custom coded and designed for each new disease or patient population, a single tRNA drug could in theory be used interchangeably across numerous disorders.
For now, that’s mostly speculative. No tRNA drugs are in the clinic. But it’s feasible and potentially impactful enough to attract a wave of interest from prominent firms. hC Bioscience joins Alltrna, launched by Flagship in November with a $50 million Series A, and ReCode Therapeutics, which has raised $160 million since 2020. Well-heeled RNA editing outfit Shape Therapeutics also has tRNA programs and Zogenix has teamed with a tiny startup called Tevard Biosciences on tRNAs for one rare form of epilepsy.
hC Bioscience comes out of work from Christopher Ahern’s lab at the University of Iowa, the same group that licensed tech to Tevard. In 2019, Ahern and postdoc John Lueck — now a co-founder and a professor at the University of Rochester — outlined a method to identify hundreds of potentially therapeutic tRNAs.
It’s co-founded and led by Leslie Williams, a longtime biotech executive who last ran ImmusanT, an ARCH-backed celiac disease biotech that quietly vanished after a Phase II trial failed in 2019.
tRNAs serve a specific function in the cell. To produce a protein, DNA transcribes a gene into mRNA and mRNA carries the instructions to the ribosome, a cell’s protein-producing factor. There, it hits a language barrier.
Both mRNA and DNA are written in nucleotides. But proteins are made up of amino acids, an entirely different class of chemical structures.
tRNA’s job is to translate between the two. It folds into a spindly 3D structure in the ribosome. For every three letters of mRNA (roughly), a strand of tRNA reaches and grabs the corresponding amino acid, building up the protein piece by piece.
hC Bioscience and the other new startups hope to intervene in a key step where that translation process can go awry. Not every three letters codes for an amino acid. Some of these triplets, also known as a codon, tell the ribosome to start making the protein in the first place, or to stop because the protein is complete.
A significant number of genetic disorders — around 10% to 15% by some estimates, including forms of cystic fibrosis and muscular dystrophy — occur because a genetic mutation has put a “stop” codon in the wrong place. tRNA doesn’t naturally bind to stop codons. So when a stop codon appears in the wrong place, the mini-factory may think its done and send the protein off unformed and ineffective.
Each new tRNA company is engineering tRNA strands that can bind to the stop codon. Ideally, in a patient, it would step in at that production step, strap the right amino acid on and allow the full-length and fully functional protein to be completed.
And because patients with different genetic diseases share the same stop codons — just place in different genes and different places in those genes — one drug could work for many different conditions.
Of course, a lot can go wrong too. The therapeutic tRNA could in theory disrupt the production of other proteins in a patient, placing an amino acid where a stop codon really did belong. And there’s the biggest question with every genetic medicine: How do you deliver it? Engineered viruses called AAVs and the lipid nanoparticles commonly used to deliver mRNA are the two clear options, but both come with drawbacks.
And there are already signs that, in some disorders, other technologies may have advantages. ReCode launched with both mRNA-based and tRNA-based therapies for cystic fibrosis, but it said in the fall it will prioritize the mRNA approach after finding better results.