Antisense Oligonucleotides for treating 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：
9912849
负责人：
Stefan M. PULST
金额：
$ 74.37万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-15 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912849
关键词：
Acute Affect Alleles Amyotrophic Lateral Sclerosis Animal Model Antisense Oligonucleotide Therapy Antisense Oligonucleotides Bacterial Artificial Chromosomes Brain Cause of Death Cells Cellular Morphology Cerebellum Cessation of life Chemistry Clinical Clinical Trials Data Disease Dose Down-Regulation Economic Burden Economics FDA approved Feasibility Studies Genes Half-Life Health Human Huntington Disease In Vitro Individual Injections Intervention Knock-out Lead Macaca fascicularis Malignant Neoplasms Modification Molecular Morphology Motor Motor Neurons Mus Mutate Myotonic dystrophy type 1 Nerve Degeneration Nervous System Heredodegenerative Disorders Neurodegenerative Disorders Neurons Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phenotype Physiological Physiology Preclinical Testing Progressive Disease Proteins Purkinje Cells Rattus Research Rodent SCA2 protein Safety Screening Result Severity of illness Site Slice Spinal Cord Spinal Muscular Atrophy Spinal cord grey matter structure Stains Symptoms Testing Therapeutic Time Tissues Toxic effect Toxicity Tests Toxicology Transgenic Mice Type 2 Spinocerebellar Ataxia Wild Type Mouse Work base design dosage effective therapy first-in-human gain of function high throughput screening human disease improved in vivo lead candidate mRNA Precursor meetings member molecular phenotype mouse model mutant neurophysiology novel therapeutics polyglutamine potency testing premature protein TDP-43 protein aggregation protein biomarkers protein expression response safety testing screening success treatment group treatment response uptake

项目摘要

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 cells (PCs) and other neurons in the cerebellum, the subcortical grey matter and spinal cord. The cause of SCA2 is a gain-of-function CAG expansion in the ATXN2 gene resulting in an expanded polyglutamine (polyQ) domain in ataxin-2. Our objective is identification of highly-potent 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 ongoing clinical trials to test ASOs for treating amyotrophic lateral sclerosis (ALS) and myotonic dystrophy type 1 (DM1), as well as the success of SPINRAZA™ (Nusinersen) for spinal muscular atrophy (SMA), the first ever FDA approved ASO drug for a neurodegenerative disorder. The feasibility of this study is based on our positive proof-of-concept data demonstrating that our lead ATXN2 ASO delays progressive rodent SCA2 motor, molecular, and neurophysiological phenotypes after symptom onset. Five specific aims are proposed: 1) an intensive in vitro screen of ASOs targeting throughout the ATXN2 pre-mRNA including cultured SCA2 patient cells, 2) in vivo screens to identify leads lowering cerebellar ATXN2 in mice, 3) safety toxicity testing in rodents and other species, 4) testing the ASO leads for delaying established SCA2 mouse motor, molecular, and neurophysiological phenotypes, and 5) GMP manufacturing of the single most potent ASO candidate and pre-investigative new drug (IND) meetings with members of the FDA. 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.

神经退行性疾病代表着不断增加的社会和经济负担，世界卫生组织估计，到 2040 年，神经退行性疾病将取代癌症成为第二大死因。在神经退行性疾病研究中，已经发现了大量的途径，但它们的直接和主要相关性与相应的人类疾病很难得到证实，并且靶向途径仍然很困难。拟议的工作将确定 2 型脊髓小脑共济失调 (SCA2) 的治疗方法，这是一种影响遗传性神经退行性疾病的方法。小脑浦肯野细胞 (PC) 和小脑、皮质下灰质和脊髓中的其他神经元 SCA2 的原因是 ATXN2 基因中的功能获得性 CAG 扩展，导致 ataxin- 中的聚谷氨酰胺 (polyQ) 结构域扩展。 2. 我们的目标是鉴定降低 ATXN2 表达的高效反义寡核苷酸 (ASO) 我们的基本原理是基于对模型生物体和人类的观察表明。更高剂量的突变等位基因/蛋白质会恶化疾病的严重程度，并且即使在小鼠出现症状后，啮齿类动物中突变polyQ蛋白表达的下调也能逆转临床表现。此外，小鼠中ATXN2的完全敲除不会导致神经变性或早产。这项研究的优点得到了正在进行的测试 ASO 治疗肌萎缩侧索硬化症 (ALS) 和强直性肌营养不良 1 型 (DM1) 的临床试验的积极结果以及成功的支持。 SPINRAZA™（Nusinersen）用于治疗脊髓性肌萎缩症（SMA），这是 FDA 批准的第一个用于治疗神经退行性疾病的 ASO 药物。这项研究的可行性基于我们积极的概念验证数据，证明我们的领先 ATXN2 ASO 可以延缓啮齿类动物的进展。症状出现后的 SCA2 运动、分子和神经生理学表型提出了五个具体目标：1）针对整个 ATXN2 前 mRNA（包括培养的）的 ASO 进行强化体外筛选。 SCA2 患者细胞，2) 体内筛选以确定降低小鼠小脑 ATXN2 的导线，3) 在啮齿动物和其他物种中进行安全性测试，4) 测试 ASO 导线延迟已建立的 SCA2 小鼠运动、分子和神经生理表型，以及 5)单一最有效的 ASO 候选药物的 GMP 生产以及与 FDA 成员的预研究新药 (IND) 会议将通过证明可行性为神经退行性疾病的治疗开辟新天地。用反义寡核苷酸靶向显性作用突变的polyQ基因。