Transfer RNA Therapies: A New Frontier in Treating Genetic Diseases

After the global spotlight on messenger RNA (mRNA) technology during the COVID-19 pandemic, a new RNA-based therapeutic is emerging in the biotech world — transfer RNA, or tRNA. While mRNA delivers genetic instructions from DNA to ribosomes, tRNA acts as the molecular bridge that decodes these instructions into amino acids, the building blocks of proteins. Recent scientific advances suggest this foundational role in protein synthesis could be harnessed to treat a range of genetic diseases.

tRNA molecules decode three-nucleotide sequences, or codons, on mRNA and deliver the corresponding amino acids during protein assembly. However, in some genetic diseases, mutations introduce premature stop codons—signals that falsely tell the ribosome to stop protein production. These mutations, known as nonsense mutations, are responsible for roughly 11% of all genetic disorders. The result is incomplete, non-functional proteins that can lead to severe health conditions like cystic fibrosis, muscular dystrophy, and certain epilepsies.

Researchers are now developing suppressor tRNAs—engineered molecules that can recognize these faulty stop signals and insert the correct amino acid, allowing the ribosome to continue assembling full-length proteins. This innovative approach, first conceptualized in the 1960s and demonstrated in animals as early as 2000, has recently become more viable thanks to advances in RNA modification and delivery technologies.

Two biotech companies, Alltrna and Tevard Biosciences, are at the forefront of this burgeoning field.

Alltrna, founded by Flagship Pioneering, aims to develop a universal tRNA therapy targeting stop codon diseases. Rather than designing a treatment for each individual condition, the company is creating engineered tRNA oligonucleotides capable of addressing multiple diseases caused by the same type of genetic mutation. Its lead candidate, AP003, has shown promising preclinical results by restoring protein production in two disease models. Delivered via lipid nanoparticles (LNPs), a method proven effective during the COVID-19 vaccine rollout, AP003 targets liver tissue—a starting point for the company due to the favorable delivery profile of RNA-based therapies in the liver.

Michelle C. Werner, Alltrna’s CEO, highlighted the adaptability of their platform, which uses machine learning to optimize the properties of tRNA molecules for better stability, efficacy, and safety. The company raised $109 million in Series B funding in 2023, signaling growing investor interest.

Tevard Biosciences, founded by MIT biologist Harvey Lodish and parents of children with Dravet syndrome, is developing two distinct tRNA-based approaches. The first is a suppressor tRNA therapy similar to Alltrna’s, targeting diseases caused by nonsense mutations. The second is an enhancer tRNA therapy for conditions stemming from haploinsufficiency, where a single functional gene copy fails to produce enough protein. Tevard’s method boosts protein production by increasing mRNA stability.

Tevard has partnered with Vertex Pharmaceuticals in a four-year collaboration focused initially on developing treatments for Duchenne muscular dystrophy (DMD) caused by nonsense mutations. The agreement includes options to expand into other forms of muscular dystrophy and additional diseases. Tevard is currently advancing its preclinical pipeline and recently relocated its headquarters to the Lilly Gateway Labs, joining Eli Lilly’s innovation hub in Boston.

Despite the promise, the field faces significant challenges. HC Bioscience, once pursuing tRNA therapies for hemophilia A and other conditions, recently shut down after its lead program failed to progress in animal studies. The primary hurdle remains efficient and targeted delivery—tRNA molecules are fragile and can trigger off-target effects if not precisely delivered.

Nonetheless, both Alltrna and Tevard are working to overcome these limitations using advanced delivery systems like LNPs and viral vectors. Regulatory bodies such as the FDA and EMA are also engaging with these companies to explore innovative clinical trial designs, including “basket trials” that group patients by mutation rather than disease type—a strategy with the potential to accelerate approval for treatments targeting ultra-rare conditions.

While tRNA-based therapies have not yet entered the clinic, early data and strategic collaborations suggest that this new class of therapeutics may soon transform the treatment landscape for a wide range of genetic diseases once considered untreatable.

Source: https://www.labiotech.eu/in-depth/trna-therapy-genetic-disease-treatment/

This is non-financial/medical advice and made using AI so could be wrong