Cathepsin O and intracranial aneurysm – COCA

Intracranial aneurysm (IA) is a cerebrovascular abnormality characterized by localized dilation and thinning of the wall of a cerebral artery affecting 3% of the population. IA is generally silent and its devastating complication is its unpredictable rupture, resulting in subarachnoid hemorrhage, fatal in 50% of cases. Unfortunately, there is no way to predict the formation and/or progression of an IA, and no pharmacological tool to limit its growth or prevent its rupture. Current treatments are invasive (surgical or endovascular) with a significant risk of procedural morbidity or mortality, making it difficult to decide whether or not to treat an unruptured IA. Although hypertension, ageing, female gender, smoking, excessive alcohol consumption and family history of aneurysm have been identified as risk factors predisposing to IA formation and rupture, the mechanisms underlying IA formation, growth and rupture are still largely unknown. Understanding these pathophysiological mechanisms of IA is a prerequisite for improved disease assessment and patient management. To address this challenge, we developed a familial approach based on whole exome sequencing which has the potential to detect rare coding variants predisposing to IA with large effect, and provide unique insights into the pathophysiology of IA. Our project is thus based on the functional analysis of causal variants we have identified in familial IA, with the objective of discovering pathways that are critical for IA development and/or rupture, identifying candidate therapeutic targets to prevent its progression, decrease the risk of rupture and optimize prognostic risk assessment of both familial and sporadic IA. By complementary approaches in vascular cells, mouse and zebrafish models, we aim at (1) discovering the role of the identified gene in vascular structure and function and (2) understanding why the variants predispose to IA.