Translational correction approaches targeting nonsense mutations in hemophilia A (TranslEight)

Severe Hemophilia A (HA) can be life-threatening or invalidating, and its current therapies, including gene therapy, have still drawbacks/limitations.

In the field of genetic disorders there is great interest on the ability of small molecules to induce “by-passing” of the wrong message, arising from the so-called nonsense mutations, by “reading through” it and restoring factor VIII (FVIII) synthesis.

These approaches would be extremely beneficial in HA, with a double relevance either for high or low responders to these strategies, a virtually unique outcome in hemophilia: i) for high responders, in terms of improvement of the disease phenotype by reaching FVIII levels overlapping or higher than the upper threshold of mild hemophilia, which would support efficient coagulation; ii) for low responders, since even residual FVIIII levels might provide protection from therapy-related immunological complications.

Here, we propose to evaluate the rescue of FVIII by challenging with “reading through” strategies a relevant number of nonsense mutations (60% of patients with this mutation type) in different experimental models exploiting the recombinant DNA technology to mimic patient mutations, cells derived from blood of HA patients and thus containing the “natural” mutation, and HA mice where patient mutations are mimicked in a system restoring circulating FVIII in plasma.

Results from this project might open new frontiers in the challenging research of treatment options for HA patients with nonsense mutations, thus laying the foundation for developing new or improving existent therapies, with important implications for patients’ quality of life.