Cerebral cavernous malformations (CCMs), also known as 'cavernous angioma' or 'cavernoma', are common vascular abnormalities found in ~0.3 - 0.9% of the population, exposing patients to a lifetime risk of hemorrhagic stroke, seizures, and other neurologic sequelae. Approximately 12% of CCM lesions present with clinically overt hemorrhage, and these cases have great likelihood of rebleed in the subsequent 5 years. There are both inherited and sporadic forms of CCM disease, and both forms are caused by somatic mutations in one of three CCM genes. The familial form of the disease is associated with multiple CCM lesions that continue to form throughout the patient's life. There is no drug treatment or cure for CCM. The current standard of care is observation of lesion number and size by magnetic resonance imaging (MRI) until one or more bleeds, often disabling, necessitate surgical intervention. Considerable progress has been made in understanding the mechanism of disease, and the CCM mutation results in over- activation of the Rho signaling pathway that regulates the endothelial cell cytoskeleton and cell- cell adhesions. There is strong proof of concept in the scientific literature (mainly from the co- applicants on this grant) that Rho kinase inhibitors will be effective in treating CCM disease. BioAxone has developed a proprietary Rho kinase inhibitor with greater specificity for ROCK2, the form of Rho kinase that is highly expressed in brain and in brain endothelial cells. Our preliminary safety data indicate that BA-1049 has a much better safety profile than Fasudil, the nonspecific ROCK1/ROCK2 inhibitor used as a research tool to explore treatment of CCM by inhibiting Rho kinase. Our goal is to test and develop BA-1049 to treat CCM and decrease the burden of disease.

Public Health Relevance

Cerebral cavernous malformation (CCM) disease is a serious genetic disease that affects 200,000 Americans, and a further 0.5% of the population has at least one sporadic CCM in their brain, with risk of rupture. There is no treatment for CCM except invasive surgery, and the development of pharmaceutical treatments for CCM is a serious unmet medical need. Rho kinase (ROCK) has been identified as a target for treatment because the genetic mutation leading to CCM causes ROCK hyper-activation in brain capillary endothelial cells. Our research consortium will examine efficacy of BioAxone's proprietary ROCK2 inhibitor for treatment of CCM in vitro and in animal models that recapitulate the human disease, and determine safety in non-GLP and GLP safety toxicology studies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZRG1)
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Fertig, Stephanie
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Bioaxone Biosciences, Inc.
United States
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Shenkar, Robert; Shi, Changbin; Austin, Cecilia et al. (2017) RhoA Kinase Inhibition With Fasudil Versus Simvastatin in Murine Models of Cerebral Cavernous Malformations. Stroke 48:187-194
Girard, Romuald; Zeineddine, Hussein A; Orsbon, Courtney et al. (2016) Micro-computed tomography in murine models of cerebral cavernous malformations as a paradigm for brain disease. J Neurosci Methods 271:14-24