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

Area of Science:

• Vascular biology
• Genetics of vascular malformations
• Pharmacology of ROCK inhibitors

Background:

• Cerebral cavernous malformations (CCMs) are vascular abnormalities linked to mutations in Ccm1, Ccm2, and Pdcd10/Ccm3 genes.
• ROCK pathway activation in endothelial cells contributes to CCM pathophysiology via non-heme iron deposition and lesion formation.
• ROCK inhibitors are being investigated as potential therapies to stabilize CCM lesions.

Purpose of the Study:

• To systematically review and evaluate the effects of ROCK inhibitors on non-heme iron deposition and lesion formation in murine CCM models.
• To assess the efficacy of direct ROCK inhibitors (e.g., fasudil, BA-1049) and indirect modulators in preclinical CCM settings.

Main Methods:

• Systematic literature review following PRISMA 2020 guidelines, registered in PROSPERO.
• Searched PubMed, Embase, Web of Science, and Scopus for studies on murine CCM models (Ccm1, Ccm2, Pdcd10/Ccm3 mutations).
• Included studies evaluating ROCK pathway modulators, assessing lesion burden, non-heme iron deposition, and ROCK activity.

Main Results:

• Four studies were included, showing fasudil consistently reduced non-heme iron deposition and lesion burden in preclinical CCM models.
• Fasudil demonstrated efficacy in Ccm1+/-Msh2-/- and Ccm2+/-Msh2-/- mice, reducing iron deposition and lesion severity.
• BA-1049 exhibited a dose-dependent reduction in non-heme iron deposition and lesion burden in a murine model.

Conclusions:

• Modulation of the RhoA/ROCK pathway effectively reduces non-heme iron deposition and lesion burden in experimental CCM models.
• ROCK inhibitors show promise as a therapeutic strategy for cerebral cavernous malformations.
• Further clinical trials are necessary to confirm these preclinical findings in human patients with CCM.