A Brain-Targeted Orally Available ROCK2 Inhibitor Benefits Mild and Aggressive Cavernous Angioma Disease

Area of Science:

• Vascular biology
• Neuroscience
• Pharmacology

Background:

• Cavernous angioma (CA) is a genetic vascular disorder caused by mutations in CCM1, CCM2, or CCM3 genes, leading to aberrant rho kinase (ROCK) activation.
• Current treatments for CA are limited to surgical resection of brain lesions, highlighting the need for novel therapeutic strategies.

Purpose of the Study:

• To investigate the efficacy of a novel ROCK2-selective inhibitor, BA-1049, in reducing brain lesion formation, growth, and maturation in preclinical models of CA.
• To explore the therapeutic potential of targeting ROCK2 signaling in CA treatment.

Main Methods:

• Genetic models of CA were established by crossing mice with mutations in CA genes (Ccm1, Ccm3) and ROCK genes (Rock1, Rock2).
• BA-1049, a ROCK2-selective inhibitor, was administered orally to Ccm1+/- and Ccm3+/- mice bred into a mutator background.
• Lesion volumes and hemorrhage were quantified using micro-computed tomography and assessment of iron deposition.

Main Results:

• Treatment with BA-1049 demonstrated a significant, dose-dependent reduction in cavernous angioma lesion volume in both Ccm1 and Ccm3 mouse models.
• BA-1049 treatment also led to a notable reduction in hemorrhage, indicated by decreased iron deposition near the lesions.
• The inhibitor effectively reduced ROCK2 activation within the brain lesions.

Conclusions:

• The ROCK2-selective inhibitor BA-1049 shows significant therapeutic promise for treating cavernous angioma.
• These findings support BA-1049 as a potential non-surgical treatment option for CA, addressing a critical unmet medical need.