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.

项目摘要 COL4A1和COL4A2突变引起的Gould综合征（GS） - 一种多系统疾病，临床疾病异质性脑血管疾病是主要结果。患有患者的脑血管疾病 GS的范围从子宫中生发基质出血引起的孔内脑，到婴儿癫痫发作，到年龄 - 相关的脑小血管疾病（CSVD）和血管认知障碍和痴呆症（VCID）。标志在患有GS的个体中观察到的CSVD包括皮质下微粒，血管周围空间肿大和 lacunar梗塞。重要的是，Col4a1突变小鼠忠实地对患者表型进行了建模。此外，Col4a1突变体小鼠患有年龄相关的脑血管功能障碍，包括肌吻合张力的丧失和高血症受损被认为对VCID进展至关重要的反应。由COL4A1和COL4A2引起的细胞外侮辱是异质和复杂的，代表基于机制的干预措施的重要障碍。但是，因为GS是毁灭性的单基因具有确定遗传原因的疾病，是通过基因组编辑技术。在此提案中，我们将利用大大改善CRISPR核，基础编辑，和Prime编辑者以及新型的病毒载体，用于使用主要GS患者细胞测试治疗方法和GS的鼠标模型。该项目将提供重要的临床前数据，以开发第一个基因组编辑 - 基于这种严重的单基因疾病的疗法。这项工作的成功完成最终可能提供一次性的终身治疗，可防止GS患者的儿童中风和与年龄有关的VCID 并创建一个纠正类似疾病的路线图。