Gene Therapy in Hutchinson-Gilford Progeria Syndrome

哈钦森-吉尔福德早衰综合症的基因治疗

基本信息

批准号：
10343225
负责人：
JONATHAN David BROWN
金额：
$ 74.24万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
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：
2022-03-15 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10343225
关键词：
2 year old 5 year old Address Adenine Adolescent Adult Age Age-Months Aging Animals Aorta Atherosclerosis Automobile Driving Base Pairing Benchmarking Biomedical Research Birth Blood Vessels Cell Count Cell Death Cells Cessation of life Child Clinical Trials Clonality DNA DNA Damage DNA strand break Data Defect Dependovirus Disease Dominant-Negative Mutation Dose Endothelial Cells Fibroblasts Fibrosis Future Genes Genetic Genetic Diseases Genome Health Hepatic Human Immune response Injections Lamin Type A Lead Leukocytes Measures Messenger RNA Mission Modeling Molecular Multiple Organ Failure Mus Mutation Nature Newly Diagnosed Nucleotides Outcome Paracrine Communication Pathogenicity Pathology Patients Phenotype Point Mutation Population Pre-Clinical Model Prevention Production Progeria Proliferating Proteins Public Health Publishing RNA Editing RNA Splicing Recovery Research Saline Smooth Muscle Myocytes Syndrome Techniques Testing Therapeutic Time Tissues Translating United States National Institutes of Health Validation Vascular Diseases Vascular Smooth Muscle Work base base editing base editor burden of illness causal variant cohort curative treatments disability disease phenotype gene therapy human disease humanized mouse improved innovation juvenile animal mature animal mortality mouse model mutant preclinical efficacy premature prevent programs protein expression senescence single-cell RNA sequencing time use treatment strategy tumorigenesis vascular smooth muscle cell proliferation

项目摘要

Project Summary and Abstract Hutchinson-Gilford Progeria Syndrome (HGPS) is an incurable, uniformly fatal disease involving a point mutation in a gene called Lamin A (LMNA). Children develop signs of HGPS typically within the two years after birth and die at a median age of 14, most commonly from progressive atherosclerotic cardiovascular disease. Although the causal mutation in HGPS was identified 18 years ago, no cures for this disease exist. Programmable base editing of DNA now enables the previously unprecedented ability to change single nucleotides in DNA and correct pathogenic mutations with DNA strand breaks. HGPS represents a tractable disease to test base editing, however it remains completely unknown whether this strategy will improve disease phenotypes associated with HGPS. As such, there is a critical need to study how DNA base editing alters the molecular defects driving HGPS in order to determine whether this genome therapy can fulfill its promise to cure disease. Our overall objective in this proposal is develop adenine base editing (ABE) as a treatment strategy for HGPS. Our central hypothesis is that ABE-treatment of adult mice can achieve sufficient editing in aortas to reverse vascular pathology through cell-autonomous effects on survival and clonal proliferation in VSMCs. Our hypothesis is formulated based on newly published and new preliminary data that demonstrate: 1) scarless correction of the pathogenic mutation by ABE in patient fibroblasts and in a humanized mouse model of HGPS; 2) prevention of vascular pathology and recovery of VSMCs at 6 months after ABE treatment of juvenile mice; 3) a significant increase in overall survival of ABE-treated juvenile animals. The rationale for this project is that validation of base editing therapies is needed to determine their potential in treating systemic human diseases. To attain our objectives, we will pursue the following two specific aims: 1) Test whether DNA editing improves vascular pathology in established disease by treating adult HGPS animals at different ages with a single injection of AAV-ABE; 2) Identify the mechanism(s) promoting VSMC recovery after ABE treatment. The overall contribution of this work will be to elucidate how adenine DNA base editing improves phenotypes in HGPS. The central innovation of this proposal is a conceptual shift in therapeutic treatment of HGPs by focusing on correcting the underlying pathogenic mutation in cells and tissues.

项目概要和摘要哈钦森-吉尔福德早衰综合症 (HGPS) 是一种无法治愈、均致命的疾病，涉及点突变存在于称为核纤层蛋白 A (LMNA) 的基因中。儿童通常在出生后两年内出现 HGPS 迹象，并且平均死亡年龄为 14 岁，最常见的是死于进行性动脉粥样硬化性心血管疾病。虽然 18 年前就发现了 HGPS 的致病突变，但目前尚无治愈这种疾病的方法。可编程底座 DNA 编辑现在能够以前所未有的方式改变 DNA 中的单核苷酸并纠正 DNA 链断裂的致病突变。 HGPS代表一种可治疗的疾病来测试碱基编辑，然而，这种策略是否会改善与相关疾病表型仍然完全未知。高压全球定位系统。因此，迫切需要研究 DNA 碱基编辑如何改变驱动 HGPS 的分子缺陷以确定这种基因组疗法是否能够兑现其治愈疾病的承诺。我们的总体目标该提案中的目标是开发腺嘌呤碱基编辑 (ABE) 作为 HGPS 的治疗策略。我们的中心假设成年小鼠的 ABE 治疗可以在主动脉中实现充分的编辑，从而通过以下方式逆转血管病理学：细胞自主对 VSMC 存活和克隆增殖的影响。我们的假设是基于新发表的新初步数据证明：1）致病突变的无痕校正在患者成纤维细胞和 HGPS 人源化小鼠模型中通过 ABE 进行检测； 2）预防血管病变以及幼年小鼠 ABE 治疗后 6 个月时 VSMC 的恢复情况； 3）整体大幅提升 ABE 处理的幼年动物的存活率。该项目的基本原理是验证碱基编辑疗法需要确定它们治疗人类系统疾病的潜力。为了实现我们的目标，我们将追求以下两个具体目标：1) 测试 DNA 编辑是否改善已建立的血管病理学通过单次注射 AAV-ABE 治疗不同年龄的成年 HGPS 动物来治疗疾病； 2) 识别 ABE 治疗后促进 VSMC 恢复的机制。这项工作的总体贡献将是阐明腺嘌呤 DNA 碱基编辑如何改善 HGPS 中的表型。本提案的核心创新点是 HGP 治疗的概念转变，重点关注纠正潜在的致病因素细胞和组织的突变。