Antisense oligonucleotides for the treatment of spinocerebellar ataxia type 2

用于治疗 2 型脊髓小脑共济失调的反义寡核苷酸

基本信息

批准号：
8683274
负责人：
Stefan M. PULST
金额：
$ 22.13万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8683274
关键词：
Affect Age Age-Months Alleles Amyotrophic Lateral Sclerosis Animal Model Antibodies Antisense Oligonucleotides Biochemical Biological Markers Bolus Infusion Brain Injuries Brain Stem Cause of Death Cerebellum Cerebrum Cessation of life Clinical Clinical Trials Control Groups Disease Disease Progression Dose Down-Regulation Economic Burden Economics Ensure Evaluation Gait Gene Mutation Genes Glial Fibrillary Acidic Protein Gliosis Health Human In Vitro Inflammation Inherited Inhibitory Concentration 50 Injection of therapeutic agent Knock-out Lead MALAT1 gene Malignant Neoplasms Modeling Molecular Monitor Motor Mus Mutate Nerve Degeneration Nervous System Heredodegenerative Disorders Neurodegenerative Disorders Neurons Normal saline Nucleic Acid Regulatory Sequences Pathway interactions Patients Pharmaceutical Preparations Phenotype Progressive Disease Proteins Purkinje Cells RNA Research Resources Rodent Rotarod Performance Test SCA2 protein Saline Severity of illness Site Spinal Muscular Atrophy Staining method Stains Testing Therapeutic Transgenic Mice Type 2 Spinocerebellar Ataxia Work base dosage endophenotype gain of function human disease in vivo molecular phenotype mouse model mutant polyglutamine premature protein expression public health relevance

项目摘要

DESCRIPTION (provided by applicant): Neurodegenerative diseases represent an ever-increasing societal and economic burden with WHO estimates indicating that they will replace cancer as the 2nd leading cause of death by 2040. In neurodegenerative disease research, a wealth of pathways has been uncovered, but their direct and primary relevance to the respective human disease has been difficult to prove and targeting of pathways has remained difficult. The proposed work will identify a treatment for spinocerebellar ataxia type 2 (SCA2), a hereditary neurodegenerative disease affecting cerebellar Purkinje neurons (PNs) and other neurons in the cerebellum, brainstem and cerebrum. The cause of SCA2 is a gain-of-function CAG expansion in the ATXN2 gene resulting in an expanded polyglutamine (polyQ) in ataxin-2. Our objective is identification of antisense oligonucleotides (ASOs) that lower ATXN2 expression. Our rationale is based on observations in model organisms and humans indicating that higher dosages of the mutant allele/protein worsen disease severity and that down-regulation of mutant polyQ protein expression in rodents reverses clinical manifestations even after mice have become symptomatic. Additionally, complete knock-out of ATXN2 in mice does not cause neurodegeneration or premature death. Merit for this study is supported by positive results in clinical trials for multiple ASOs, and ongoing clinical trials to test ASOs for the treatment of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). The feasibility is based on established resources including lead ASOs identified in vitro and a well-characterized human-BAC transgenic mouse model with late onset progressive motor phenotypes. Three specific aims are proposed: 1) Identification of the 4 most effective ASOs for lowering ATXN2 expression, from 15 lead ASOs that we have already identified in a preliminary ASO screen, 2) testing the ASO leads for amelioration of a biochemical endophenotype that includes indication of maintained glial health, and 3) testing the two most effective ASOs for ameliorating a motor phenotype in an SCA2 mouse BAC model. The proposed work will break new ground for treatment of neurodegenerative diseases by demonstrating feasibility of targeting dominant-acting mutated polyQ genes with antisense oligonucleotides.

描述（由申请人提供）：神经退行性疾病代表着一种不断增强的社会和经济负担，谁估计，他们将取代癌症，因为到2040年，第二个主要的死亡原因。在神经退行性疾病研究中，许多途径已经发现了很多途径，但与人类疾病的直接和原始相关性与相关的人类疾病变得困难，并且始终存在着一项困难。拟议的工作将确定针对2型脊椎没收（SCA2）的治疗方法，一种影响小脑Purkinje神经元（PNS）的遗传神经退行性疾病和小脑，脑干和小脑中的其他神经元。 SCA2的原因是ATXN2基因中功能的CAG膨胀，导致双生-2中的聚谷氨酰胺（PolyQ）扩展。我们的目标是鉴定降低ATXN2表达的反义寡核苷酸（ASO）。我们的理由是基于模型生物和人类的观察结果，表明较高的突变等位基因/蛋白质的剂量恶化了疾病的严重程度，并且在啮齿动物中突变polyq蛋白表达的下调即使在小鼠成为症状后，啮齿动物中的突变剂也会逆转临床表现。另外，在小鼠中完全敲除ATXN2不会导致神经变性或过早死亡。这项研究的优点得到了多个ASO的临床试验的积极结果，以及正在进行的临床试验，用于测试ASO的肌萎缩性侧索硬化症（ALS）和脊柱肌肉萎缩（SMA）。可行性基于已建立的资源，包括在体外鉴定的铅ASO和具有较晚发作性运动表型的特征良好的人-BAC转基因小鼠模型。 Three specific aims are proposed: 1) Identification of the 4 most effective ASOs for lowering ATXN2 expression, from 15 lead ASOs that we have already identified in a preliminary ASO screen, 2) testing the ASO leads for amelioration of a biochemical endophenotype that includes indication of maintained glial health, and 3) testing the two most effective ASOs for ameliorating a motor phenotype in an SCA2 mouse BAC model.拟议的工作将通过证明用反义寡核苷酸靶向显性作用的突变PolyQ基因的可行性来打破新的治疗神经退行性疾病的基础。