Alltrna Unveils First-in-Class tRNA Candidate with Broad Nonsense Mutation Readthrough Activity Across Multiple Rare Diseases at ASGCT

Monogenic diseases are genetic disorders caused by mutations in a single gene. Nonsense mutations are one of the main types of such gene mutations, leading to premature termination of protein translation and resulting in truncated proteins. This, in turn, generates premature termination codons (PTCs), which account for approximately 11% of monogenic diseases, including conditions such as cystic fibrosis, Duchenne muscular dystrophy, and β-thalassemia. PTC-related diseases are characterized by simple mutation types and have a relatively high incidence, making them an important target for treating monogenic disorders.

Suppressor-tRNA can induce readthrough of nonsense mutations. Its sequence is mostly identical to natural tRNA, but its anticodon can recognize stop codons (UAG, UGA, UAA) through base pairing. Therefore, when the ribosome encounters a PTC during translation, suppressor-tRNA can introduce the corresponding amino acid into the growing peptide chain, inducing readthrough to produce a functional full-length protein.

▲ Figure | Suppressive tRNA can read through premature stop codons to restore full-length protein expression (Source: Nature Biotechnology)

Recently, at the ASGCT 2023 conference, byFlagship PioneeringSupported, committed to the development of tRNA therapies startupAlltrnaAlltrna's platform, supported by machine learning (ML), can design, modify, produce, and deliver engineered tRNA oligonucleotides with significantly enhanced potency and activity, capable of reading through premature stop codons and restoring full-length protein expression.

AlltrnaDemonstrating that its designed tRNA oligonucleotides exhibit universal readthrough activity on shared gene mutations across 25 disease models, 14 different genes, and 7 distinct mutation sites on a single gene, regardless of the gene or specific location.

AlltrnaFounded in 2018 at Flagship Labs. Its innovative ideas originated from members of FP's entrepreneurial scientist team.Theonie Anastassiadis, she is also currently the co-founder and Chief Innovation Officer of Alltrna. In 2021, the company announced the completion of a $50 million financing round and officially came out of stealth mode.

Anastassiadis began focusing on tRNA several years ago. While fascinated by the properties and functions of tRNA, she also questioned why no one in the industry was studying it. Thanks to her efforts,AlltrnaStart running inside FP. "There are over 600 different tRNA genes in the human genome, and tRNA is the most abundant RNA in cells. But humans only need 47 different tRNAs to translate mRNA into proteins." Anastassiadis said that the modifiable sites of tRNA diversity lay the foundation for its engineering.

Its CEOLovisa AfzeliusHaving worked at major pharmaceutical companies such as Pfizer and AstraZeneca, with 20 years of experience in the pharmaceutical industry.

In addition,AlltrnaIn August 2022, Joanne Protano, former Senior Vice President of Finance and Operations at Rubius Therapeutics, was appointed as Chief Financial Officer; in October of the same year, Dr. Caroline Köhrer was appointed as Vice President of the Discovery Platform. Köhrer worked at MIT for 20 years, researching protein synthesis across all fields of life.

Alltrna"The data shows that their machine learning can optimize the sequence of tRNA, significantly enhancing the activity of engineered tRNA. 'One of the current focuses is how to further expand the therapeutic window using sequences and chemical modifications in tRNA,' said Anastassiadis. 'We have also built a very comprehensive molecular profiling platform to monitor any type of NTC (natural termination codon) readthrough and the expression of other proteins.'"

The idea of using suppressor tRNA activity to correct human diseases dates back about 40 years to the laboratory of Yuet Wai Kan (简悦威) at the University of California, San Francisco.

In 1982, Yuet Wai Kan proposed the idea of using tRNA to treat β-thalassemia; in the early 2000s, researchers at the University of Colorado validated the feasibility of tRNA therapy in transgenic mice; in 2002, Anton Kiselev and others from the Ott Institute of Obstetrics and Gynecology in St. Petersburg, Russia, used mutant suppressor tRNA to treat nonsense mutation DMD mice; in 2014, Portuguese researchers showed that suppressor tRNA could be used to treat hereditary cancers caused by nonsense mutations.

But tRNA has never attracted much attention, or perhaps the technology at the time was not ready.

Nowadays, withReCode Therapeutics、Shape Therapeutics、Tevard BiosciencestRNA therapy companies represented by Alltrna have started to gain attention. Tevard has also previously partnered with Vertex to develop a tRNA therapy for DMD.

However, despite the great potential exhibited by tRNA, it remains uncertain whether it will outperform small molecule readthrough drugs.PTC TherapeuticsThe developed Translarna (ataluren) is a small molecule drug for patients with nonsense mutation-mediated DMD, which has been approved for marketing in Europe and Brazil.