Development of BA-1049 for treatment of cerebral cavernous malformation

BA-1049治疗脑海绵状血管瘤的开发

基本信息

批准号：
9320314
负责人：
ISSAM A AWAD
金额：
$ 143.07万
依托单位：
BIOAXONE BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9320314
关键词：
Affect American Animal Model Biological Assay Biological Markers Blinded Blood Vessels Blood capillaries Brain Brain hemorrhage CCM1 gene Canis familiaris Capillary Endothelial Cell Cavernous Hemangioma Cell-Cell Adhesion Clinical Pathology Clinical Trials Complementary DNA Cytochrome P450 Cytoskeleton DNA Sequence Alteration Data Defect Deposition Development Disease Dose Endothelial Cells Gene Silencing Genes Goals Grant Health Hemorrhage Hereditary Disease Histology Human In Vitro Infiltration Inflammatory Inherited Intellectual Property Iron Kidney Lead Lesion Life Literature Location Lung Magnetic Resonance Imaging Mediating Medical Middle Cerebral Artery Occlusion Mus Mutation Myosin Light Chains Neurologic Operative Surgical Procedures Oral Outcome Pathology Patients Permeability Pharmaceutical Preparations Pharmacologic Substance Pharmacology Pharmacotherapy Phase Phenotype Phosphorylation Pilot Projects Placebos Plasma Population Process Property Protein Isoforms ROCK1 gene Rattus Recovery Research Rho-associated kinase Risk Route Rupture Safety Seizures Signal Pathway Small Interfering RNA Somatic Mutation Specificity Stress Fibers Techniques Telemetry Testing Therapeutic Effect Toxic effect Toxicokinetics Toxicology Transfection Transgenic Organisms adducin base brain endothelial cell burden of illness capillary cerebral capillary cerebral cavernous malformations cerebrovascular clinically relevant fasudil gene function genotoxicity human disease immunocytochemistry in vivo indexing inhibitor/antagonist intraperitoneal kinase inhibitor lifetime risk loss of function meetings monolayer mouse model phase 2 study pre-clinical preclinical efficacy preclinical safety research study response rho safety study standard of care subcutaneous success therapeutic target tool vascular abnormality

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由适用提供）：脑海绵状畸形（CCMS），也称为“海绵状血管瘤”或“海绵体”，是约0.3-0.9％的常见血管异常，占患者的终身性感，癫痫发作，癫痫发作和其他神经学sequelae的终生风险。大约有12％的CCM病变出现临床明显的出血，这些病例在随后的5年中很有可能被重新出现。 CCM疾病的遗传性和零星形式既是遗传性的形式，两种形式都是由三个CCM基因之一中的体细胞突变引起的。该疾病的家庭形式与多种CCM病变有关，这些病变在整个患者的生活中继续形成。 CCM没有药物治疗或治疗。当前的护理标准是通过磁共振成像（MRI）观察病变的数量和大小，直到一个或多个出血，通常会禁用，必要的手术干预。在理解疾病的机理方面取得了长足的进步，CCM突变导致RHO信号传导途径过多激活，该途径调节内皮细胞细胞骨架和细胞细胞粘附。科学文献中有强有力的概念证明（主要来自这笔赠款的共同申请者），Rho激酶抑制剂将有效治疗CCM疾病。生物酮已经开发了一种专有的Rho激酶抑制剂，对Rock2的特异性较高，Rock2是Rho激酶的形式，在大脑和脑内皮细胞中高度表达。我们的初步安全性数据表明，BA-1049的安全性要比Fasudil（非特异性Rock1/Rock2抑制剂）用作研究工具的安全性要好得多，该工具通过抑制Rho激酶来探索CCM的处理。我们的目标是测试和开发BA-1049来治疗CCM并减少疾病的燃烧。