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Therapeutic targeting of ATXN2 for sporadic amyotrophic lateral sclerosis (ALS)

ATXN2 治疗散发性肌萎缩侧索硬化症 (ALS) 的靶向治疗

基本信息

批准号：
10056164
负责人：
Amy Elizabeth Taylor
金额：
$ 3.84万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-16 至 2023-12-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10056164
关键词：
ALS patients Adult Amyotrophic Lateral Sclerosis Animal Model Antisense Oligonucleotide Therapy Antisense Oligonucleotides Biological CDK5 gene Cell Nucleus Cells Cellular Assay Cellular biology Clinic Clinical Clinical Trials Cytoplasm Disease Down-Regulation Excision Exhibits Genes Genetic Genetic Transcription Human Knowledge Lead Length Mass Spectrum Analysis Messenger RNA Modeling Modification Motor Neurons Muscle Weakness Nature Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Nuclear RNA Pathogenesis Pathologic Pathology Pathway interactions Patients Pattern Phenotype Phosphorylation Physicians Proteins Proteomics Publishing RNA-Binding Proteins Research Respiratory Failure Risk Role SCA2 protein Sampling Scientist Series Site Spinal Cord Symptoms Testing Therapeutic Therapeutic Uses Tissues Toxic effect Training Treatment Efficacy Work Yeast Model System design disease heterogeneity experimental study genomic signature human tissue induced pluripotent stem cell inhibitor/antagonist insight knock-down neuronal survival neuropathology neurotoxicity overexpression patient population patient stratification patient subsets polyglutamine protein TDP-43 proteomic signature response screening success targeted treatment therapeutic target therapy development transcriptomics

项目摘要

Project Summary / Abstract Amyotrophic lateral sclerosis (ALS) is a fatal, adult onset, neurodegenerative disease for which there is currently no cure and very limited treatment options. Patients present with increasing muscle weakness and die from respiratory failure within 3-5 years post symptom onset. Currently, the majority of ALS research is focused on genetic causes, which account for approximately only 10% of cases (familial), without any treatment developments for the remaining 90% of patients (sporadic). Although nothing is known about the pathogenesis or propagation of disease, 97% of all patients share one pathological hallmark: TDP-43 mislocalization. TDP-43 is an essential RNA binding protein that in healthy patients is expressed in spinal cord and cortical motor neuron nuclei. In ALS it is mislocalized to the cytoplasm where it forms distinct phosphorylated aggregates which may be toxic to the neurons. Recently, Ataxin-2 (ATXN2) has been identified as a potential modulator of TDP-43 toxicity in yeast and animal models. To support this finding, 5% of patients with ALS have intermediate length repeat expansions in the polyQ region of the gene, compared to 2% of non-neurological controls. Furthermore, our group and others have demonstrated that regardless of repeat length, ALS patients demonstrate perturbations in the distribution of ATXN2 in motor neurons. Taken together, these suggest that ATXN2 may be a candidate for antisense oligonucleotide (ASO) therapeutic potential, however, the question remains as to whether therapy would benefit all sporadic patients or be dependent on polyQ length. This project proposes a series of experiments designed to examine ATXN2 as a potential therapeutic target in human tissue directly from patients with disease, comparing patients with and without intermediate length repeat expansions. The aims will explore target characterization and phenotype by examining expression levels and pathways involved in disease. The proposal examines target engagement via knocking down levels of ATXN2 and related proteins in the pathway and exploring the changes in genomic and proteomic signature to develop a disease cellular profile. Lastly, it will verify target efficacy with ATXN2-targeted ASO treatment in order to identify the subset of patients likely to benefit from therapy. Due to the devastating nature of ALS it is imperative that research focus on therapeutic potential in a directly translatable manner in order to expedite treatments for current patients. This proposal will stratify the patient population of those likely to benefit from ATXN2 directed therapy, however, the field remains optimistic that removal of ATXN2 will benefit all patients, not just the small percentage of those with intermediate length repeats. This directly translatable proposal, along with monthly patient contact in the largest ALS clinic in San Diego, will provide ideal physician scientist training in a collaborative research and clinical setting.

项目摘要/摘要