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（由申请人提供）：脑海绵状血管瘤 (CCM)，也称为“海绵状血管瘤”或“海绵体瘤”，是约 0.3 - 0.9% 人口中常见的血管异常，使患者终生面临出血性中风的风险、癫痫发作和其他神经系统后遗症，大约 12% 的 CCM 病变表现为临床明显出血， CCM 疾病有遗传性和散发性两种形式，这两种形式都是由三个 CCM 基因之一的体细胞突变引起的。该疾病的家族性形式与多种疾病相关。 CCM 病变在患者的一生中持续形成。目前的治疗标准是通过磁共振成像 (MRI) 观察病变的数量和大小，直到出现一次或多次出血，通常会导致患者致残。在理解疾病机制方面已经取得了相当大的进展，并且 CCM 突变导致调节内皮细胞骨架和细胞间粘附的 Rho 信号通路过度激活。科学文献（主要来自本次资助的共同申请人）表明 Rho 激酶抑制剂将有效治疗 CCM 疾病 BioAxone 开发了一种专有的 Rho 激酶抑制剂，对 ROCK2 具有更高的特异性，在大脑和脑内皮细胞中高度表达的 Rho 激酶形式，我们的初步安全性数据表明 BA-1049 比 Fasudil（一种用作探索治疗的研究工具的非特异性 ROCK1/ROCK2 抑制剂）具有更好的安全性。通过抑制 Rho 激酶来测试和开发 BA-1049 来治疗 CCM 并减轻疾病负担。