Gene therapy for disorders of the extracellular matrix

细胞外基质疾病的基因治疗

基本信息

批准号：
10658481
负责人：
Douglas Gould
金额：
$ 248.13万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658481
关键词：
Ablation Address Affect Alleles Basement membrane Binding Blood Vessels Blood brain barrier dysfunction Brain Brain hemorrhage Cell Line Cell model Cell physiology Cells Cerebral small vessel disease Cerebrovascular Disorders Cerebrovascular system Chemicals Childhood stroke Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collagen Collagen Type IV Complex DNA Data Development Disease Distal Dominant-Negative Mutation Dose Endothelial Cells Etiology Evaluation Extracellular Matrix Eye Gene Targeting Genes Genetic Glycine Gould Syndrome Hemorrhage Heterozygote Histologic Human Impairment Individual Intervention Kidney Knockout Mice Knowledge Lacunar Infarctions Lead Life Location Mediating Mendelian disorder Modeling Molecular Molecular Chaperones Mus Mutant Strains Mice Mutate Mutation Organ Other Genetics Outcome Pathology Pathway interactions Patients Perinatal subependymal hemorrhage Phenotype Physiological Point Mutation Pre-Clinical Model Protein Region Proteins Quality Control RNA Resources Route Seizures Signal Transduction Skeletal Muscle System Technology Testing Therapeutic Intervention Vascular Cognitive Impairment Viral Vector White Matter Hyperintensity Work adeno-associated viral vector age related base editor candidate identification cerebral microbleeds cerebrovascular disease phenotype dominant genetic mutation extracellular gene correction gene therapy genome editing genome wide association study genome-wide improved in utero in vivo infancy innovation mouse model mutant next generation novel nuclease personalized medicine pre-clinical prevent prime editor promoter response solid state therapeutic evaluation therapeutic genome editing vascular cognitive impairment and dementia white matter injury

项目摘要

PROJECT SUMMARY COL4A1 and COL4A2 mutations cause Gould syndrome (GS) – a multisystem disorder for which clinically heterogeneous cerebrovascular disease is the major consequence. Cerebrovascular disease in individuals with GS can range from porencephaly caused by germinal matrix hemorrhages in utero, to infantile seizures, to age- related cerebral small vessel disease (cSVD) and vascular cognitive impairment and dementia (VCID). Hallmarks of cSVD observed in individuals with GS include subcortical microbleeds, enlarged perivascular spaces, and lacunar infarcts. Importantly, Col4a1 mutant mice faithfully model patient phenotypes. Moreover, Col4a1 mutant mice have age-related cerebrovascular dysfunction including loss of myogenic tone and impaired hyperemic responses that are thought to be critical to VCID progression. The extracellular insults resulting from COL4A1 and COL4A2 are heterogeneous and complex, which represents a significant barrier to mechanism-based interventions. However, because GS is a devastating monogenic disease with a defined genetic cause, it is an ideal candidate for correction of the root cause of the disease via genome editing technologies. In this proposal, we will leverage vastly improved CRISPR nucleases, base editors, and prime editors along with novel viral vectors to test therapeutic approaches using primary GS patient cells and mouse models of GS. This project will provide important pre-clinical data to develop the first genome editing- based therapy for this severe monogenic disorder. The successful completion of this work could eventually provide a one-time, lifelong treatment that prevents both childhood stroke and age-related VCID for GS patients and create a roadmap for correction of similar diseases.

项目概要 COL4A1 和 COL4A2 突变导致古尔德综合征 (GS)——一种多系统疾病，临床上异质性脑血管疾病是患有脑血管疾病的个体的主要后果。 GS 的范围包括子宫内生发基质出血引起的孔脑畸形、婴儿癫痫发作、年龄相关性癫痫。相关脑小血管疾病（CSVD）和血管性认知障碍和痴呆（VCID）。在 GS 个体中观察到的 cSVD 包括皮质下微出血、血管周围间隙扩大和重要的是，Col4a1 突变小鼠忠实地模拟了患者表型。小鼠患有与年龄相关的脑血管功能障碍，包括肌源张力丧失和充血受损被认为对 VCID 进展至关重要的反应。 COL4A1 和 COL4A2 引起的细胞外损伤是异质且复杂的，这代表然而，由于 GS 是一种破坏性的单基因药物，因此这是基于机制的干预措施的一个重大障碍。具有明确遗传原因的疾病，它是通过以下方式纠正疾病根本原因的理想候选者：在本提案中，我们将利用大幅改进的 CRISPR 核酸酶、碱基编辑器、和 Prime 编辑器以及新型病毒载体，使用原代 GS 患者细胞测试治疗方法该项目将为开发第一个基因组编辑提供重要的临床前数据。这项工作最终可能会成功完成。为 GS 患者提供一次性终身治疗，预防儿童期中风和年龄相关的 VCID 并制定纠正类似疾病的路线图。