Combined HMG-COA reductase and prenylation inhibition in treatment of CCM

Significance

Cerebral cavernous malformations (CCMs) are common vascular anomalies of the central nervous system that can lead to seizures, focal neurological deficits, and brain hemorrhage. Clinical options are limited mainly to treatment of symptoms or surgical resection, and targeted pharmacological therapy is lacking. Here we undertake a high-throughput screen and identify fluvastatin and zoledronate, two drugs already approved for clinical use for other indications, which act synergistically to reverse outcomes of CCM3 loss. Used in combination, fluvastatin and zoledronate effectively attenuate neural and vascular deficits in mouse models of CCM in vivo, significantly reducing formation of lesions and extending longevity. Our studies suggest that combined therapy targeting the mevalonate pathway might have therapeutic effects in CCM disease.

Abstract

Cerebral cavernous malformations (CCMs) are common vascular anomalies that develop in the central nervous system and, more rarely, the retina. The lesions can cause headache, seizures, focal neurological deficits, and hemorrhagic stroke. Symptomatic lesions are treated according to their presentation; however, targeted pharmacological therapies that improve the outcome of CCM disease are currently lacking. We performed a high-throughput screen to identify Food and Drug Administration-approved drugs or other bioactive compounds that could effectively suppress hyperproliferation of mouse brain primary astrocytes deficient for CCM3. We demonstrate that fluvastatin, an inhibitor of 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase and the N-bisphosphonate zoledronic acid monohydrate, an inhibitor of protein prenylation, act synergistically to reverse outcomes of CCM3 loss in cultured mouse primary astrocytes and in Drosophila glial cells in vivo. Further, the two drugs effectively attenuate neural and vascular deficits in chronic and acute mouse models of CCM3 loss in vivo, significantly reducing lesion burden and extending longevity. Sustained inhibition of the mevalonate pathway represents a potential pharmacological treatment option and suggests advantages of combination therapy for CCM disease.