Project 2: Therapeutic Gene Editing for Friedreich's Ataxia

项目 2：弗里德赖希共济失调的治疗性基因编辑

基本信息

批准号：
10668768
负责人：
DAVID R LIU
金额：
$ 64.66万
依托单位：
JACKSON LABORATORY
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：
2023-05-16 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668768
关键词：
15 year old Acceleration Adolescent Adverse event Affect Age Years Alleles Ataxia Biodistribution Biological Models Capsid Cardiomyopathies Cells Clinic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Diabetes Mellitus Disease Disease Progression Dose Event Friedreich Ataxia Gene Expression General Population Genes Genome Genomics Goals Heart Inherited Spinocerebellar Degenerations Interruption Introns Investigation Investigational Drugs Late-Onset Disorder Lead Length Life Expectancy Mediating Methods Modification Mus Muscle Weakness Nervous System Newborn Infant Onset of illness Operative Surgical Procedures Outcome Pancreas Pathogenicity Patients Phenotype Physical therapy Proteins Research Personnel Resources Route Safety Sensory Somatic Cell Spinal Ganglia Symptoms Technology Therapeutic Tissues Toxic effect Trinucleotide Repeats Triplet Multiple Birth United States Up-Regulation Work adeno-associated viral vector autosome base editing base editor cell type delivery vehicle design frataxin gene complementation gene repression genome editing improved in vivo innovation knock-down lead candidate mouse model nervous system disorder overexpression pre-clinical preclinical development preclinical safety prime editing prime editor protein expression spasticity therapeutic development therapeutic gene therapeutic genome editing tool transcriptomics vector

项目摘要

PROJECT SUMMARY PROJECT 2 (FRDA) Friedreich's Ataxia (FRDA) is an autosomal recessive disorder characterized by progressive ataxia and damage to the nervous system, that is often associated with muscle weakness, spasticity, cardiomyopathy and diabetes mellitus. FRDA is caused by a deficiency in frataxin (FXN) protein levels that usually arises from a GAA-triplet repeat expansion in intron 1 of the FXN gene which results in transcriptional repression. The length of FXN GAA- repeats in the general population ranges from ~5-60, while FRDA patients may present with 66 to well over 1200 repeats, typically 600 to 900 repeats long. Long GAA-repeats undergo progressive instability in some somatic cell types that predominantly results in repeat expansion and consequently loss of FXN protein. The tissues that are affected in FRDA include the dorsal root ganglia (DRGs), the heart, and the pancreas. The onset of disease in patients is anticorrelated with the length of the shortest FXN allele, which typically presents at 10-15 years of age, though approximately 25% of patients have an atypical presentation with later disease onset. Although some symptoms can be ameliorated by physical therapy and surgery, no effective cure or treatment for the broader FRDA phenotype has yet been approved. The life expectancy for patients with FRDA is typically 40-50 years of age. In this follower project, we aim to improve FXN protein expression to enable rescue of disease progression in FRDA patients. Specifically, we aim to: (1) Optimize genome editing strategies to correct FRDA repeat expansion; (2) optimize genome editing strategies to correct FRDA repeat expansion in mice; and (3) perform pre-clincial IND enabling studies to assess safet and efficacy. We will work closely with the Gene Editing Core to develop the latest base editing and/or prime editing technologies in FRDA model systems. We will iterate with the Gene Editing Core to ensure that our genome editing tools maximize on-target editing efficiencies, minimize undesirable gene editing byproducts and off-target editing events, and maximize compatibility with in vivo delivery methods of potential therapeutic relevance.

项目摘要项目2（FRDA）弗里德里希（Friedreich 对于神经系统，通常与肌肉无力，痉挛，心肌病和糖尿病有关 Mellitus。 FRDA是由Frataxin（FXN）蛋白水平的缺乏引起的，通常由GAA-毛皮引起在FXN基因的内含子1中重复扩展，从而导致转录抑制。 FXN GAA-的长度一般人群的重复范围为〜5-60，而FRDA患者可能有66名至1200多个患者重复，通常长600至900个重复。长GAA重复在某些体细胞中发生渐进式不稳定性主要导致重复膨胀并因此丧失FXN蛋白的细胞类型。组织在FRDA中受到影响包括背根神经节（DRG），心脏和胰腺。疾病的开始在患者中，患者与最短的FXN等位基因的长度是反相关的，通常在10 - 15年的时间内呈现。年龄，尽管大约25％的患者患有非典型疾病发作的非典型表现。尽管可以通过物理疗法和手术来改善某些症状，但无法治愈或治疗对于更广泛的FRDA表型，尚未获得批准。 FRDA患者的预期寿命通常为 40-50岁。在这个追随者项目中，我们旨在改善FXN蛋白表达，以挽救疾病进展 FRDA患者。具体而言，我们的目标是：（1）优化基因组编辑策略以纠正FRDA重复扩张; （2）优化基因组编辑策略以纠正小鼠的FRDA重复扩展；（3）执行界限前的研究能够评估安全性和功效。我们将与基因编辑核心紧密合作开发FRDA模型系统中最新的基础编辑和/或主要编辑技术。我们会迭代基因编辑核心，以确保我们的基因组编辑工具最大化目标编辑效率，请最小化不良基因编辑副产品和脱靶编辑事件，并最大程度地兼容体内潜在治疗相关性的输送方法。