Exploring base editing for the correction of nonsense mutations in hemophilia B

Nonsense mutations, accounting for ~11% of all described disease-causing gene lesions, are caused by in-frame premature termination codons (PTCs) that may elicit an abnormal termination of protein synthesis, leading to the potential absence of a gene product or the production of truncated proteins. On the other hand, PTC-bearing transcripts can be down-regulated by nonsense-mediated mRNA decay. These elements contribute to shape the outcome of inherited disorders, in particular of X-linked diseases, by leading to the so-called “null” conditions. The aim is to explore the base editing approach for hemophilia B, in which this strategy has never been tempted so far. Noticeably, consistently with the low therapeutic threshold needed to ameliorate the disease phenotype, it is relevant to note that the output of mRNA base editing is predicted to produce functional factor IX levels compatible with a mild hemophilia B forms.