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Development of a novel gene therapy for the treatment of tauopathy

开发治疗 tau 蛋白病的新型基因疗法

基本信息

批准号：
10526133
负责人：
Mohammad Moshahid Khan
金额：
$ 30.8万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
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：
2022-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10526133
关键词：
Acute Advanced Development Adverse effects Adverse event Affect Alzheimer&apos s Disease Antisense Oligonucleotides Atherosclerosis Behavioral Binding Blood - brain barrier anatomy Brain Catalytic DNA Characteristics Chronic Clinical Clinical Research Code Cognitive Cognitive deficits Data Deposition Development Disease Disease Progression Dose Drug Kinetics FTD with parkinsonism Foundations Frequencies Frontotemporal Dementia Genetic Goals Human Impaired cognition In Vitro Individual Inflammatory Injections Intervention Label Literature Malignant Neoplasms Memory Memory impairment Messenger RNA Metabolic Clearance Rate Motor Multiple Sclerosis Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Oligonucleotides Organ Outcome Study Pathologic Pathology Patients Pharmacodynamics Production Proteins Public Health Publishing Quality of life RNA Research Safety Single-Stranded DNA Symptoms Tauopathies Technology Testing Therapeutic Therapeutic Index Therapeutic Intervention Transcript Transgenes Transgenic Mice Translating base clinically significant cognitive function cytokine design effective therapy gene therapy improved in vitro testing in vivo knock-down mouse model mutant nervous system disorder neurochemistry neuropathology novel overexpression pharmacokinetics and pharmacodynamics pre-clinical prevent progressive neurodegeneration protein expression relating to nervous system response safety study selective expression side effect spatial memory targeted treatment tau Proteins tau aggregation tau expression tau mutation therapy development uptake

项目摘要

Tauopathies, including frontotemporal dementia and Alzheimer's disease (AD), are neurodegenerative diseases characterized by abnormal deposition of tau protein in the brains of affected individual. Currently, there is no therapeutic interventions that prevent tauopathies or slow its progression. The intensity of tau burden strongly correlates with cognitive impairment and progressive neuropathological symptoms, thus supporting the development of therapies targeting pathological tau. We have been examining an alternative approach for tauopathy gene therapy that involves the use of DNAzymes (DNZs), which cross the blood-brain barrier and have been shown to be effective in treating multiple sclerosis, cancer and atherosclerosis. DNAzymes – RNA- cleaving single-stranded DNA oligonucleotides– are a relatively novel and underutilized therapeutic molecule that can be designed to cleave mRNA transcripts to regulate the expression of protein it codes for. The advantages of DNZs over other gene therapies are their catalytic activity, leading to a better dose-response efficacy; stability and systemic delivery to all organs including brain thus, avoiding the need for direct CNS injection. DNAzymes thus represent a novel gene therapy approach that can be used to reduce levels of mRNA for disease-causing proteins. Based on above observation, we propose that DNAzymes can be designed to regulate the expression of human tau proteins by selectively targeting their mRNAs transcripts and ameliorate neurodegeneration and cognitive deficits in a mouse model of tauopathy. In our preliminary studies, we have designed a novel and specific anti-human tau DNZ (TDNZ) targeting the 1N4R transgene of human tau expressing the P301S mutation and showed that TDNZ effectively cleave human tau mRNA in vitro and in vivo. The objective of this application is to determine whether TDNZ targeting mutant human tau can prevent cognitive deficits and neuropathology characteristics of tauopathies in a preclinical mouse model of tauopathy. In Aim 1, we will determine distribution, stability and safety of TDNZ delivery as well as efficacy needed to maintain therapeutic knockdown. In Aim 2, we will assess benefit by extent of human Tau mRNA and protein knockdown in the brain, cognitive function and brain neurochemistry and pathology in PS19Tg mice. Based on the expected outcomes, these studies will help advance the development of DNZs as a disease modifying treatment for tauopathy, as well as provide foundational studies for the clinical use of DNZs in other primary tauopathies and, potentially, other neurological diseases.

包括额颞叶痴呆和阿尔茨海默病(AD)在内的神经官能症是神经退行性疾病以患者大脑中tau蛋白的异常沉积为特征。目前，没有预防或减缓肌萎缩侧索硬化症的治疗干预。牛磺酸负担的强度很强与认知障碍和进行性神经病理症状相关，从而支持针对病理性tau的治疗方法的发展。我们一直在研究另一种方法来包括使用脱氧核酶(DNZs)的互动式基因疗法，它可以跨越血脑屏障，并已被证明在治疗多发性硬化症、癌症和动脉粥样硬化方面有效。DNAzyme-RNA- 裂解单链DNA寡核苷酸是一种相对新颖且未得到充分利用的治疗分子这可以被设计为切割mRNA转录本，以调节其编码的蛋白质的表达。这个与其他基因疗法相比，DNZ的优势在于它们的催化活性，导致了更好的剂量反应功效、稳定性和全身给药至包括大脑在内的所有器官，从而避免了直接使用中枢神经系统注射。因此，DNAzyme代表了一种新的基因治疗方法，可用于降低mRNA水平致病蛋白质。基于以上观察，我们认为DNAzyme可以被设计成通过选择性靶向其mRNAs转录本调控人tau蛋白的表达肌萎缩侧索硬化症小鼠模型的神经退行性变和认知缺陷。在我们的初步研究中，我们有设计了一种针对人tau基因1N4R的新型特异性抗人tau DNZ(TDNZ) 表达了P301S突变，表明TDNZ在体外和体内都能有效切割人tau基因。这项应用的目的是确定靶向突变型人tau的TDNZ是否可以防止认知临床前肌萎缩侧索硬化症小鼠模型中肌萎缩侧索硬化症的缺陷和神经病理学特征。在目标1中，我们将确定TDNZ的分布、稳定性和安全性以及维持所需的有效性治疗性击倒。在目标2中，我们将通过敲除人Tau mRNA和蛋白质的程度来评估益处在脑中，PS19Tg小鼠的认知功能和脑神经化学和病理学。基于预期的结果，这些研究将有助于推动DNZ作为一种疾病修正治疗的发展并为DNZ在其他原发牛顿病中的临床应用提供基础研究，有可能是其他神经系统疾病。