SBIR-STTR Award

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 Statement:


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.

Project Terms:
adducin; Affect; American; Animal Model; base; Biological Assay; Biological Markers; Blinded; Blood capillaries; Blood Vessels; Brain; Brain hemorrhage; burden of illness; Canis familiaris; capillary; Capillary Endothelial Cell; Cavernous Hemangioma; CCM1 gene; Cell-Cell Adhesion; cerebral capillary; cerebral cavernous malformations; cerebrovascular; Cerebrum; Clinical Pathology; Clinical Trials; clinically relevant; Complementary DNA; Cytochrome P450; Cytoskeleton; Data; Defect; Deposition; Development; Disease; DNA Sequence Alteration; Dose; Endothelial Cells; fasudil; gene function; Gene Silencing; Genes; genotoxicity; Goals; Grant; Hemorrhage; Hereditary Disease; Histology; Human; human disease; immunocytochemistry; In Vitro; in vivo; indexing; Infiltration; Inflammatory; Inherited; inhibitor/antagonist; Intellectual Property; intraperitoneal; Iron; Kidney; kinase inhibitor; Lead; Lesion; Life; Lifetime Risk; Literature; Location; loss of function; Lung; Magnetic Resonance Imaging; Mediating; Medical; meetings; Middle Cerebral Artery Occlusion; monolayer; mouse model; Mus; Mutation; Myosin Light Chains; Neurologic; Operative Surgical Procedures; Oral; Outcome; Pathology; Patients; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacotherapy; Phase; phase 2 study; Phenotype; Phosphorylation; Pilot Projects; Placebos; Plasma; Population; pre-clinical; preclinical efficacy; preclinical safety; Process; Property; Protein Isoforms; public health relevance; Rattus; Recovery; Research; research study; response; rho; Rho-associated kinase; Risk; ROCK1 gene; Route; Rupture; Safety; safety study; Seizures; Signal Pathway; Small Interfering RNA; Somatic Mutation; Specificity; standard of care; Stress Fibers; subcutaneous; success; Techniques; Telemetry; Testing; Therapeutic Effect; therapeutic target; tool; Toxic effect; Toxicokinetics; Toxicology; Transfection; Transgenic Organisms; vascular abnormality

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 Statement:


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.

NIH Spending Category:
Brain Disorders; Cerebrovascular; Genetics; Neurosciences

Project Terms:
adducin; Affect; American; Animal Model; base; Biological Assay; Biological Markers; Blinded; Blood capillaries; Blood Vessels; Brain; brain endothelial cell; Brain hemorrhage; burden of illness; Canis familiaris; capillary; Capillary Endothelial Cell; Cavernous Hemangioma; CCM1 gene; Cell-Cell Adhesion; cerebral capillary; cerebral cavernous malformations; cerebrovascular; Clinical Pathology; Clinical Trials; clinically relevant; Complementary DNA; Cytochrome P450; Cytoskeleton; Data; Defect; Deposition; Development; Disease; DNA Sequence Alteration; Dose; Endothelial Cells; fasudil; gene function; Gene Silencing; Genes; genotoxicity; Goals; Grant; Health; Hemorrhage; Hereditary Disease; Histology; Human; human disease; immunocytochemistry; In Vitro; in vivo; indexing; Infiltration; Inflammatory; Inherited; inhibitor/antagonist; Intellectual Property; intraperitoneal; Iron; Kidney; kinase inhibitor; Lead; Lesion; Life; Lifetime Risk; Literature; Location; loss of function; Lung; Magnetic Resonance Imaging; Mediating; Medical; meetings; Middle Cerebral Artery Occlusion; monolayer; mouse model; Mus; Mutation; Myosin Light Chains; Neurologic; Operative Surgical Procedures; Oral; Outcome; Pathology; Patients; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacotherapy; Phase; phase 2 study; Phenotype; Phosphorylation; Pilot Projects; Placebos; Plasma; Population; pre-clinical; preclinical efficacy; preclinical safety; Process; Property; Protein Isoforms; Rattus; Recovery; Research; research study; response; rho; Rho-associated kinase; Risk; ROCK1 gene; Route; Rupture; Safety; safety study; Seizures; Signal Pathway; Small Interfering RNA; Somatic Mutation; Specificity; standard of care; Stress Fibers; subcutaneous; success; Techniques; Telemetry; Testing; Therapeutic Effect; therapeutic target; tool; Toxic effect; Toxicokinetics; Toxicology; Transfection; Transgenic Organisms; vascular abnormality