Using siRNAs against tau circular RNAs as a rational therapy for Alzheimer's disease

使用针对 tau 环状 RNA 的 siRNA 作为阿尔茨海默病的合理疗法

基本信息

批准号：
10484224
负责人：
Stefan Stamm
金额：
$ 39.52万
依托单位：
CIRCCURE CORPORATION
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：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10484224
关键词：
Address Adenosine Adult Agreement Alu Elements Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Alzheimer&apos s disease therapy Binding Biological Assay Brain Cause of Death Cell model Cells Chemistry Clinical Complex Data Ensure Epigenetic Process Exons Genes Glioblastoma Human In Vitro Incubators Injections Inosine Investigational New Drug Application Kentucky Legal Legal patent Logistics MAPT gene Mediating Messenger RNA Methods Microtubules Modification Molecular Monitor Mus Neurofibrillary Tangles Nose Oligonucleotides Pathologic Pharmaceutical Preparations Pharmacology Phase Primates Production Property Proteins RNA RNA Editing Research Ribose Safety Side Site Small Business Technology Transfer Research Small Interfering RNA Small RNA Tauopathies Testing Therapeutic Toxic effect Translating Universities Vertebral column Walking Work base chemical standard circular RNA cost cross reactivity design dosage human model in vivo in vivo Model innovation neuroblastoma cell neurofibrillary tangle formation neuron loss phase 1 study phase 2 study prevent protein aggregation response siRNA delivery tau Proteins tau aggregation uptake

Address Adenosine Adult Agreement Alu Elements Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Alzheimer&apos s disease therapy Binding Biological Assay Brain Cause of Death Cell model Cells Chemistry Clinical Complex Data Ensure Epigenetic Process Exons Genes Glioblastoma Human In Vitro Incubators Injections Inosine Investigational New Drug Application Kentucky Legal Legal patent Logistics MAPT gene Mediating Messenger RNA Methods Microtubules Modification Molecular Monitor Mus Neurofibrillary Tangles Nose Oligonucleotides Pathologic Pharmaceutical Preparations Pharmacology Phase Primates Production Property Proteins RNA RNA Editing Research Ribose Safety Side Site Small Business Technology Transfer Research Small Interfering RNA Small RNA Tauopathies Testing Therapeutic Toxic effect Translating Universities Vertebral column Walking Work base chemical standard circular RNA cost cross reactivity design dosage human model in vivo in vivo Model innovation neuroblastoma cell neurofibrillary tangle formation neuron loss phase 1 study phase 2 study prevent protein aggregation response siRNA delivery tau Proteins tau aggregation uptake

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项目摘要

Summary: The formation of neurofibrillary tangles (NFT) formed by aggregation of the microtubule-associated protein tau (MAPT) is a hallmark of Alzheimer’s disease (AD) and the likely cause of neuronal death. Currently, there are no rational treatments available that directly target NFT formation and thus address the direct molecular cause for AD. Based on our academic research, we will develop an siRNA-based product that can be delivered nasally and prevents NFT formation in early stages of AD. In prior studies, we identified human-specific circular RNAs from the MAPT gene that are generated through backsplicing of exon 12 to either exon 7 or exon 10. These tau circRNAs are translated after epigenetic modifications that change adenosine residues to inosines (A>I editing). The translated proteins correspond to multimers of the microtubule-binding domain and promote NFT formation. Our company, CircCure, will develop siRNAs that selectively target tau circRNAs and thus prevent NFT formation; we will test this product in two specific aims: Aim #1: Define the optimal siRNA backbone sequence for the 12->7 and 12->10 tau circRNA by performing an oligo-walk to identify the backbone sequence with the highest efficacy toward tau circRNAs and lowest efficacy against linear RNAs. After undergoing standard chemical optimization, in Aim #2, we will test the siRNA efficacy (IC50) using intranasal and injection delivery in an in vivo model of human neuroblastoma cells grafted in mouse brains. This product is highly innovative, as it will directly address NFT formation targeting recently discovered circular RNAs. The final product of these Phase I studies will be an siRNA that can be delivered intranasally that reduces tau circRNAs and NFT formation in human cells embedded in a mouse brain. The product will thus directly target the cause of neuronal death in AD, which will provide supportive evidence for Phase II studies, where we will test pharmacology and safety to prepare for an investigational new drug (IND) application.

概括：由微管相关的聚集形成的神经纤维缠结（NFT）的形成蛋白质tau（MAPT）是阿尔茨海默氏病（AD）的标志，也是神经元死亡的可能原因。现在，没有可直接针对NFT形成的理性治疗 AD的分子原因。根据我们的学术研究，我们将开发一种基于SIRNA的产品通过鼻腔交付，可防止在AD的早期阶段进行NFT形成。在先前的研究中，我们从MAPT基因中鉴定出人类特异性的圆形RNA。通过外显子12到外显子7或外显子10的后置。这些tau circrnas在表观遗传后翻译将腺苷残留物更改为插入的修改（a> i编辑）。翻译的蛋白质对应于微管结合域的多聚体并促进NFT形成。我们的公司Circcure将开发有选择地针对tau circrnas的sirnas，从而防止NFT 形成；我们将以两个特定的目的测试该产品：目标＃1：定义最佳siRNA骨干序列对于12-> 7和12-> 10 tau circrna，通过执行寡核步行以鉴定与骨干序列 tau circrnas的效率最高，对线性RNA的效率最低。经过标准后化学优化，在AIM＃2中，我们将使用鼻内和注射递送测试siRNA效率（IC50）人类神经母细胞瘤细胞的体内模型移植在小鼠大脑中。该产品具有很高的创新性将直接解决靶向最近发现的圆形RNA的NFT形成。这些阶段研究的最终产品将是可以在鼻内传递的siRNA 减少包包在小鼠脑中的人类细胞中的tau circrnas和NFT形成。因此，产品将直接针对AD中神经元死亡的原因，这将为II期研究提供支持证据，我们将在其中测试药理学和安全，以准备投资新药（IND）应用。