2026 Poster Presentations
P482: RHO-ASSOCIATED KINASE INHIBITORS IN CEREBRAL CAVERNOUS MALFORMATIONS: A PRECLINICAL SYSTEMATIC REVIEW
Irem Uslu1; Ecem Senturk2; Bilge Kara, MD3; Merve G Turkmenel4; Zeynep E Celikkiran5; Berkay Kilic6; Doga D Demir Yangi, MD7; Kivanc Yangi, MD8; 1Pamukkale University, School of Medicine; 2Lobachevsky University, School of Medicine; 3Manavgat State Hospital; 4Atilim University, School of Medicine; 5Biruni University, School of Medicine; 6Istanbul University-Cerrahpasa, Cerrahpasa School of Medicine; 7Ivy Brain Tumor Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center; 8Department of Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center
Introduction: Cerebral cavernous malformations (CCMs) are clusters of dilated capillaries that may occur sporadically or from loss-of-function mutations in specific genes, most commonly CCM1, CCM2, and PDCD10/CCM3. CCMs may present with acute or chronic intracranial hemorrhage (ICH), and symptoms can include headaches, seizures, hearing or vision changes, and weakness, among others. In CCMs, lesion development is previously linked to Rho-associated protein kinase (ROCK) activation in endothelial cells, and ROCK inhibitors have recently been proposed as potential stabilizing agents to reduce lesion burden and non-heme iron deposition. This study investigates the effects of ROCK inhibition on lesion burden and iron deposition in murine CCM models.
Methods: This study followed PRISMA guidelines and was registered in PROSPERO. PubMed, Embase, Web of Science, and Scopus were searched from inception until September 4, 2025. We included preclinical murine CCM studies focusing on CCM1, CCM2, or PDCD10/CCM3 mutations, encompassing heterozygous and homozygous knockouts as well as conditional and transgenic models. In vitro studies investigating the ROCK pathway in CCM models were also deemed eligible. Studies were included if they investigated ROCK inhibitors, independent of the specific drug, dosage, route of administration, or treatment duration. The primary outcome was intralesional non-heme iron accumulation, with lesion number and size assessed as secondary outcomes.
Results: Of the 373 records identified, four preclinical studies were deemed eligible and included in the analysis. In Ccm1+/−Msh2−/− mice, fasudil significantly reduced non-heme iron deposition (P<0.01) and decreased mature stage 2 lesions by 74% compared with placebo (P=0.02). Comparable results were observed in Ccm2+/−Msh2−/− mice, where fasudil lowered both non-heme iron deposition (P=0.028) and lesion burden (P=0.039). One study further demonstrated a complete absence of extravascular iron deposits with fasudil (P=0.03) along with reduced lesion counts (P=0.049). BA-1049, a fasudil-related Rho-kinase inhibitor, also showed dose-dependent reductions in non-heme iron deposition (P≤0.037) and lesion burden (P=0.022) relative to placebo.
Conclusion: Our results indicate that ROCK inhibitors, particularly Fasudil, may reduce lesion burden and intralesional non-heme iron deposition in CCM murine models. These findings suggest that ROCK inhibition could represent an alternative strategy for stabilizing bleeding risk in CCMs and potentially slowing disease progression, although confirmation in prospective clinical trials is still needed.