Current and Future Treatment Options for Cerebral Cavernous Malformations

Cerebral cavernous malformations (CCMs) are vascular lesions associated with seizures, hemorrhage, and neurologic deficits. The familial form of CCM constitutes ≈20% of cases and presents with multifocal lesions in the brain and spinal cord, whereas the more common sporadic form typically involves a single lesion. Treatments of CCM include surgical resection and stereotactic radiosurgery, as well as management of symptoms (eg, seizures). Surgical resection or irradiation of lesions in eloquent areas requires careful consideration because of the potential for morbidity and mortality, and these treatments are not advised for asymptomatic lesions. The purpose of this narrative review is to describe the current state of treatments for CCM, with an emphasis on potential clinically relevant pharmacologic treatments aimed at targeting aberrant molecular signaling associated with CCM. Literature was identified through PubMed using search terms related to treatments of CCMs. In endothelial cells, overactivation of RhoA/Rho‐associated kinase contributes to disruption of cell‐cell junctions and a shift to a senescence‐associated secretory phenotype, which leads to inflammation, migration, and invasiveness of mutant endothelial cells. Specific (NRL‐1049) and nonspecific (fasudil, statins) inhibition of Rho‐associated kinase has shown effectiveness to reduce lesion burden in mouse models of CCM. A phase 1/2 clinical trial is currently underway to investigate the efficacy of atorvastatin in patients with CCM, and a first‐in‐human clinical trial to evaluate safety, tolerability, and pharmacokinetic parameters of NRL‐1049 began in 2023. The β‐blocker propranolol and the superoxide dismutase mimetic REC‐994 have also shown effectiveness in attenuating lesion burden in preclinical studies. Results from a pilot phase 2 clinical trial of propranolol support further investigation in an adequately powered trial, and the safety, pharmacokinetics, and potential efficacy of REC‐994 are currently being evaluated in a phase 2 clinical trial. Additional agents have been used solely in preclinical models and require clinical evaluation.