NoStop: Personalised Small Molecule Gene Therapy

Premature termination codons (PTCs) account for 10–20% of genetic disease cases and represent a major mechanism of tumor suppressor gene inactivation. A therapeutic approach capable of reverting PTCs into sense codons would have broad applicability, benefiting millions of patients across diverse genetic disorders and cancers. Readthrough therapy offers this potential; however, its clinical impact has so far been limited by disappointing trial outcomes.Using a combination of in-house–developed high-throughput human readthrough assays and machine learning, we recently demonstrated that a key factor underlying this limited success is the strong sequence specificity of readthrough drugs, which varies markedly among compounds. With the NoStop platform, our goal is to build on this validated technology to transform the readthrough therapy field by systematically generating comprehensive PTC-specificity maps for all known readthrough compounds, while simultaneously establishing a sequence-tailored high-throughput drug discovery pipeline to identify novel proprietary readthrough drugs. If successful, NoStop will generate invaluable data to enable the transition of readthrough therapy from a one-size-fits-all approach to a personalized medicine paradigm.