Available treatments for psoriasis are mainly focused in targeting key immune players. However, the appearance over time of negative side effects, such as immunosuppression, affects patients health and quality of life.
Keratinocytes actively participate in the inflammatory loops involved in the pathogenesis of psoriasis. Our studies have uncovered TREX2, a keratinocyte-specific exonuclease, as a novel target for innovative skin-site psoriasis treatments. Blocking TREX2 can be as effective as treatments targeting the immune system, while avoiding their adverse immunosuppressive effects.
- To develop a first-in-class small molecule inhibiting TREX2, a keratinocyte-specific exonuclease, as a novel, safe and effective treatment for psoriasis.
Problem to Solve
Psoriasis is a chronic inflammatory skin disease that affects about 3% of the population. It is characterized by skin lesions that may involve any part of the body with a different range of severity. Present treatments target key players and pathways of the immune system, but they are not tissue specific and can cause immunosuppression with an increased risk of infections and cancer. These and other limitations, like non-responder patients, loss of efficacy, relapse and toxicity in the long term, affects patients health and quality of life. For this reason, a more effective, specific, well-tolerated and safer therapy is needed.
By means of drug discovery approaches, the team has identified compounds that selectively block TREX2 activity and significantly reduce psoriatic inflammation in the IL23-induced mouse model of psoriasis in a TREX2 dependent manner, as no effects are observed in the TREX2 knockout mice.
The project pursues to develop highly selective, effective and safe TREX2 small molecule inhibitors for a reliable skin-directed psoriasis therapy to be proposed for future clinical trials.