Development of BA for treatment of cerebral cavernous malformation

DESCRIPTION provided by applicant Cerebral cavernous malformations CCMs also known as andapos cavernous angiomaandapos or andapos cavernomaandapos are common vascular abnormalities found in of the population exposing patients to a lifetime risk of hemorrhagic stroke seizures and other neurologic sequelae Approximately of CCM lesions present with clinically overt hemorrhage and these cases have great likelihood of rebleed in the subsequent 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 patientandapos 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 ROCK the form of Rho kinase that is highly expressed in brain and in brain endothelial cells Our preliminary safety data indicate that BA has a much better safety profile than Fasudil the nonspecific ROCK ROCK inhibitor used as a research tool to explore treatment of CCM by inhibiting Rho kinase Our goal is to test and develop BA to treat CCM and decrease the burden of disease PUBLIC HEALTH RELEVANCE Cerebral cavernous malformation CCM disease is a serious genetic disease that affects Americans and a further 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 BioAxoneandapos s proprietary ROCK 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