The pursuit of non-invasive treatment for intracranial aneurysms to PRevent aneurYSMal subarachnoid hemorrhage

Rupture of intracranial aneurysms (IA) results in aneurysmal subarachnoid hemorrhage (aSAH), an often fatal type of stroke. Invasive IA treatment to prevent aSAH is a high-risk procedure, limiting its use and leaving most IA patients untreated. Thus, there is an urgent need for non-invasive drugs preventing aSAH, but these are lacking as our understanding of the causal disease pathways is poor. The considerable female predominance in IA and aSAH suggests the existence of sex-specific regulation of these pathways. In the ERC PRYSM StG we identified candidate drugs lisinopril, amlodipine, tamsulosin, simvastatin and metformin associated with a reduced risk of aSAH. These targets have an inhibitory effect on the Transforming Growth Factor-β (TGF-β) pathway, a potent inducer of Endothelial-to-Mesenchymal transition (EndMT), a driver of vascular disease. The Treat-PRYSM team’s main aim is to transition the research from the ERC PRYSM StG into innovation by performing the following activities: 1)Confirm and validate our 5 candidate drugs—lisinopril, amlodipine, tamsulosin, simvastatin and metformin—as effective drugs in reducing aSAH incidence, by employing the principle of drug repurposing and triangulating evidence from epidemiological and genetic data.2)Find genetic evidence that the EndMT and TGF-β pathways are involved in IA pathogenesis, thereby identifying these pathways as potential therapeutic targets for the candidate drugs, using a large-scale genomics approach. 3)Determine whether the mode of action of the candidate drugs and EndMT/TGF-β pathways is influenced by sex.4)Evaluate the opportunities for a clinical trial of the most promising candidate drug to assess its ability to inhibit growth of IAs, serving as a surrogate marker for rupture. This approach will ultimately provide a non-invasive, cost-effective drug to prevent aSAH in patients with unruptured IAs and will significantly enhance our understanding of the disease's causal pathways.