US-based biotechnology company Alltrna is developing transfer RNA (tRNA)-based therapies that aim to offer a broad solution for thousands of rare genetic diseases by targeting common mutations rather than addressing each disease individually.
The goal of the approach is to overcome the limitations of traditional rare disease therapies, which typically focus on single diseases, making it difficult to develop treatments for the vast majority of rare genetic conditions.
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Currently, only 5% of the known genetic diseases have an US Food and Drug Administration (FDA)-approved therapy, according to rare disease non-profit organisation Global Genes. Alltrna’s approach seeks to change this by focusing on nonsense mutations – premature stop codons – which occur in about 10% of genetic diseases and impact an estimated 30 million people worldwide, according to Alltrna’s CEO Michelle Werner.
“In the rare disease setting, there are somewhere around 10,000 different genetic conditions. Even with novel technologies like gene therapy, gene editing, or mRNA, each must address a specific gene or disease,” said Werner. “That’s why only 5% of these diseases have an approved therapy – most remain overlooked and underserved.”
Alltrna’s engineered tRNA technology is designed to read through premature stop codons and restore normal protein production. These specific mutations are found across a range of genetic diseases, making a mutation-focused approach potentially more efficient than developing separate therapies for each disease, explained Werner.
“Our engineered tRNAs can be used across multiple diseases, genes, and mutation locations”, Werner explained. “This represents a far more universal tool to treating patients by taking a mutation-specific approach, rather than a disease-specific approach.”
In December 2024, Alltrna presented preclinical data on its first tRNA candidate, AP003. The chemically modified, engineered tRNA, delivered via a lipid nanoparticle, demonstrated in vivo restoration of protein production in mouse models of two stop codon diseases, methylmalonic acidaemia (MMA) and phenylketonuria (PKU).
One of the interesting parts of Alltrna’s approach is the potential to study these therapies in basket trials, which can group patients with different diseases but with the same underlying genetic mutation. This trial design is commonly used in oncology but has been less explored in rare diseases.
“We’re really working through what that preclinical data package needs to be in order for us to support a broad number of diseases to be included in that basket trial,” highlighted Werner.
She said that Alltrna is working closely with global regulators, including the FDA and European Medicines Agency (EMA), to navigate the complexities of designing such trials. Regulators recognise the challenges of drug development for ultra-rare patients and are encouraging strategies that can address multiple diseases at once, Werner noted.
Other companies are also developing therapies using this approach. In March 2023, Tevard Biosciences entered a four-year global research collaboration with Vertex Pharmaceuticals to develop novel tRNA-based treatments for Duchenne muscular dystrophy caused by nonsense mutations.
Cell & Gene Therapy coverage on Pharmaceutical Technology is supported by Cytiva.
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