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一种不断增加的社会和经济燃烧，据估计，他们将取代癌症作为到2040年的第二个主要死亡原因。在神经退行性疾病研究中，已经发现了许多途径，但是与各自的人类疾病的直接和主要相关性很难证明和靶向途径，这是困难的。拟议的工作将确定针对2型脊髓脑性共济失调（SCA2），一种影响小脑Purkinje细胞（PC）的遗传神经退行性疾病（PC）和其他神经元的治疗方法。 SCA2的原因是ATXN2基因中功能的CAG扩展，导致ataxin-2中的聚谷氨酰胺（PolyQ）结构域扩展。我们的目标是鉴定降低ATXN2表达的高功能反义寡核苷酸（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/蛋白质疾病严重程度不良的剂量以及啮齿动物中突变体polyq蛋白表达的下调，即使小鼠成为症状后，啮齿动物中的polyq蛋白表达也会逆转临床表现。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正在进行的临床试验的积极结果的支持，以测试ASO，用于治疗1型1型（DM1）以及Spinraza™（Nusinersen）的成功，用于治疗肌萎缩性侧面硬化症（ALS）和肌动型增生症（DM1），脊柱肌肉萎缩症（SMA）的成功率是Frofy（SMA），这是有史以来第一次批准的fda SASOED auter demerer auter auter。这项研究的可行性是基于我们的积极概念证明数据，表明我们的铅ATXN2 ASO延迟了症状发作后的渐进性啮齿动物SCA2运动，分子和神经生理学表型。提出了五个具体目的：1）在整个ATXN2前MRNA中的ASOS靶向的大量体外筛选，包括培养的SCA2患者细胞，2）在体内筛选，以鉴定小鼠降低小脑ATXN2的铅，3）啮齿动物和其他物种的安全性sabecors and ASO的安全性，4）测试ASO的SCA2小鼠，4）表型和5）GMP制造最重要的ASO候选者和与FDA成员的感染前新药（IND）会议。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。