Rho-associated kinase inhibitors in cerebral cavernous malformations: a preclinical systematic review

Clinical Snapshot

Key Findings

• P Value: Not reported

• Effect Size: Not quantified in abstract

• Primary Outcome: Lesion burden consistently reduced by fasudil across CCM mouse models

• Nnt Or Sensitivity: Dose-dependent reduction demonstrated with BA-1049

• Confidence Interval: Not reported

Clinical Application

Fasudil is available but requires clinical trials for CCM indication Would require TGA approval for CCM indication; currently no PBS listing for this indication; RACGP guidelines do not address ROCK inhibitors for CCM Currently limited to research settings; not applicable to clinical practice

Abstract

Cerebral cavernous malformations (CCMs) are vascular abnormalities characterized by clusters of dilated capillaries. They are most associated with loss-of-function mutations in three genes (Ccm1, Ccm2, and Pdcd10/Ccm3). In capillary endothelial cells, mutations activate the Rho-associated coiled-coil-containing protein kinase (ROCK), leading to non-heme iron deposition and lesion formation, thereby contributing to CCM pathophysiology. To address this, ROCK inhibitors are being explored as potential stabilizing therapies in CCM. By reviewing the existing literature, this study aims to provide a descriptive evaluation of their effects on non-heme iron deposition and lesion formation in murine models. This systematic review followed the PRISMA 2020 guideline and was registered in PROSPERO (CRD420251048073). PubMed, Embase, Web of Science, and Scopus were searched from inception to 2 February 2026. Eligible studies included in vivo murine CCM models with mutations in the Ccm1, Ccm2, and Pdcd10/Ccm3 genes. Studies had to evaluate direct ROCK inhibitors, such as fasudil and BA-1049, or indirect modulators of the RhoA/ROCK pathway, such as statins, regardless of dosage, route, or duration, and provide molecular evidence of RhoA/ROCK pathway modulation. The primary outcome was lesion burden, and the secondary outcomes included non-heme iron deposition and ROCK activity. Systematic searches identified 389 records, of which 4 studies were included, demonstrating that fasudil, a ROCK inhibitor, consistently reduced non-heme iron deposition and lesion burden in preclinical CCM models in mice. In Ccm1+/-Msh2-/- mice, fasudil reduced non-heme iron deposition and stage 2 lesions; in Ccm2+/-Msh2-/- mice, fasudil reduced non-heme iron deposition and lesion burden. One study demonstrated that BA-1049 caused a dose-dependent reduction in non-heme iron deposition and lesion burden. Studies have shown that ROCK pathway modulation reduces non-heme iron deposition and lesion burden. Further clinical investigations involving patients with CCM are essential to verify whether these experimental benefits can be reproduced in clinical settings.

References

1. 1.Uslu, I., Senturk, E., Celikkiran, Z. E., Kara, B., Turkmenel, M. G., Kilic, B., Alomari, O., Demir Yangi, D. D., & Yangi, K. (2026). Rho-associated kinase inhibitors in cerebral cavernous malformations: a preclinical systematic review. Neurosurgical Review. https://doi.org/10.1007/s10143-025-03688-7