Modeling and Therapeutic Approaches for Genetic Vasculopathies

遗传性血管病的建模和治疗方法

基本信息

批准号：
10706537
负责人：
MARK E LINDSAY
金额：
$ 69.62万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10706537
关键词：
Actins Adolescent Affect Age Alleles Anesthesia procedures Animal Model Aorta Aortic Aneurysm Arginine Arteries Behavioral Biological Models Bladder Blood Blood Pressure Blood Vessels Blood flow Brain Brain Infarction Bundling CRISPR/Cas technology Cardiovascular Diseases Carotid Arteries Cell Line Cell model Cell physiology Cellular Assay Cerebral small vessel disease Cerebrovascular Circulation Cerebrovascular Disorders Cerebrovascular system Cerebrum Cessation of life Characteristics Child Childhood Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collagen Complex Custom DNA Sequence Alteration Data Deposition Development Diagnosis Dilatation - action Disease Disease Progression Dominant-Negative Mutation Elasticity Elastin Evaluation Exhibits Eye Functional disorder Gene Targeting Genes Guide RNA Heterozygote Histidine Histopathology Home Homeostasis Hypotension Impaired cognition Impairment In Vitro Infarction Intestines Ipsilateral Ischemia Ischemic Stroke Knock-in Knock-out Lead Life Ligation LoxP-flanked allele Lung Measures Mediating Medical Microvascular Dysfunction Modeling Molecular Mus Muscle Mutation Mydriasis Natural History Neurologic Neurology Operative Surgical Procedures Organ Oxygen Patent Ductus Arteriosus Pathogenicity Pathology Patient observation Patients Performance Pericytes Phenotype Prevention Publishing Pupil Rare Diseases Recurrence Rupture Shapes Smooth Muscle Smooth Muscle Myocytes Stroke Stroke prevention Study models Syndrome System Systemic blood pressure Therapeutic Uterus Variant Vascular Diseases Woman adeno-associated viral vector base editing body system brain abnormalities cerebrovascular disability early onset experience functional outcomes gene correction gene therapy genetic approach human disease improved in vivo mortality mouse model mutant neurovascular neurovascular coupling novel palliate pre-clinical predictive marker respiratory secondary endpoint vascular abnormality white matter injury

项目摘要

Summary Smooth Muscle Dysfunction Syndrome is a rare disease with less than 50 known cases worldwide. It is caused by a specific genetic mutation in the ACTA2 gene that affects smooth muscle cells. Smooth muscle cells are found in many different organs in the body. These include the large blood vessels that carry blood around the body (aorta), brain blood vessels, lungs, eye pupil muscles, gut, bladder and even the womb in women. The children affected by this specific ACTA2 mutation have very complex medical problems involving many body systems. Patients experience repeated strokes as blood vessels supplying the brain are abnormal in shape and narrowed. As adolescents, the aorta can weaken and dissect, requiring major surgery. Some children have need respiratory support or home oxygen. These children suffer from a severe complex disease that can result in progressive neurological disability. Our aim is to develop a gene therapy for children with ACTA2 disease that can treat all the different organs affected. In this proposal we will extensively characterize in vitro ACTA2R179H smooth muscle cell function (AIM1), evaluate the neurovascular and subsequent behavioral consequences of the ACTA2R179H mutation in a novel mouse model (AIM2), and finally use the ACTA2R179H mouse model to study the ischemic strokes (AIM3). To investigate therapeutic options throughout the proposal we will utilize a novel CRISPR-cas9 system with custom guide RNAs to revert (base editing) or destroy (allele targeting) the ACTA2R179H allele, delivering the system in vitro and in vivo, and quantitatively measuring the phenotypic consequences of gene targeting

概括平滑肌功能障碍综合征是一种罕见的疾病，在全球范围内少于50例已知病例。它是造成的通过影响平滑肌细胞的ACTA2基因中的特定遗传突变。平滑肌细胞是在体内许多不同的器官中发现。这些包括大血管，这些血管在周围携带血液身体（主动脉），脑血管，肺，瞳孔肌肉，肠道，膀胱，甚至是女性的子宫。这受这种特定ACTA2突变影响的儿童具有许多身体的非常复杂的医学问题系统。患者经历了反复的中风，因为供应大脑的血管形状异常，并且狭窄。作为青少年，主动脉可以削弱和剖析，需要进行大手术。有些孩子有需要呼吸支持或家用氧气。这些孩子患有严重的复杂疾病，可能导致在渐进的神经疾病中。我们的目的是为Acta2疾病儿童开发基因疗法可以治疗受影响的所有不同器官。在此提案中，我们将广泛表征体外的特征 ACTA2R179H平滑肌细胞功能（AIM1），评估神经血管和随后的行为在新型小鼠模型中ACTA2R179H突变的后果（AIM2），最后使用 ACTA2R179H小鼠模型研究缺血性中风（AIM3）。调查治疗选择在整个提案中，我们将利用具有自定义指南RNA的新颖的CRISPR-CAS9系统来恢复（基础编辑）或破坏（靶向等位基因）ACTA2R179H等位基因，在体外和体内传递系统定量测量基因靶向的表型后果