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.

包括额颞痴呆和阿尔茨海默氏病（AD）在内的陶氏病是神经退行性疾病其特征在于受影响个体的大脑中tau蛋白的异常沉积。目前，没有治疗干预措施可防止扭曲或减缓其进展。 Tau Burnen的强度强烈与认知障碍和进行性神经病理学症状相关，从而支持靶向病理tau的疗法的发展。我们一直在研究一种替代方法涉及使用dnazymes（DNZ）的Tauopathy基因疗法，该疗法穿过血脑屏障和已显示可有效治疗多发性硬化症，癌症和动脉粥样硬化。 dnazymes - RNA- 切割单链DNA寡核苷酸 - 是一种相对新颖的热分子可以设计以清除mRNA转录物来调节IT代码的蛋白质的表达。这 DNZ比其他基因疗法的优点是它们的催化活性，导致剂量反应更好效率;因此，稳定性和全身向包括大脑在内的所有器官传递，避免需要直接CNS 注射。因此，dnazymes代表了一种新型的基因治疗方法，可用于降低mRNA水平用于引起疾病的蛋白质。基于上述观察，我们建议可以将Dnazymes设计为通过选择性靶向其mRNA转录并改善，调节人tau蛋白的表达在小鼠模型中，神经变性和认知缺陷。在我们的初步研究中，我们有设计了一种针对人tau的1N4R变换的新颖而特定的反人类Tau DNZ（TDNZ）表达P301S突变，并表明TDNZ在体外和体内有效清除人tau mRNA。该应用的目的是确定靶向突变人类tau的tdnz是否可以预防认知 tauopathy的临床前小鼠模型中的Tauopathies的缺陷和神经病理学特征。在AIM 1中，我们将确定TDNZ交付的分配，稳定性和安全性以及维护所需的便利性治疗性敲低。在AIM 2中，我们将根据人tau mRNA和蛋白质敲低的程度评估受益在大脑中，PS19TG小鼠的认知功能和脑神经化学和病理学。基于预期结果，这些研究将有助于推进DNZ的发展，作为一种修改疾病的治疗方法 Tauopathy，并提供基础研究，用于在其他原发性tauopathies中临床使用DNZ，并提供可能是其他神经系统疾病。