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TDP-43 Proteinopathy in ALS-FTD: Mechanism, Target Validation and Biomarker

ALS-FTD 中的 TDP-43 蛋白病：机制、靶标验证和生物标志物

基本信息

批准号：
10583597
负责人：
PHILIP C WONG
金额：
$ 124.58万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583597
关键词：
ALS patients Adult Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease related dementia Amyotrophic Lateral Sclerosis Amyotrophic Lateral Sclerosis Pathway Autopsy Behavior Biological Assay Biological Markers C9ORF72 Cerebrospinal Fluid Clinical Clinical Trials Compensation Complement Critical Pathways Cross-Sectional Studies Cytoplasm DNA DNA-Binding Proteins Data Dementia Deterioration Development Diagnosis Disease Enzyme-Linked Immunosorbent Assay Exhibits Exons Frontotemporal Dementia Frontotemporal Lobar Degenerations Genes Goals Grant Immune Sera Injections Knowledge Language Malignant Neoplasms Molecular Monitor Monoclonal Antibodies Motivation Motor Neuron Disease Motor Neurons Mus Neurodegenerative Disorders Neurofilament-H Nuclear Pathogenicity Pathologic Pathology Patient Recruitments Patients Peptides Personality Phase Phosphorylation Proteins Proxy Publishing RNA Splicing RNA-Binding Proteins Reagent Repression Response Elements Series Spinal Staging Symptoms Tars Testing Therapeutic Time Transactivation Validation Vertebral column Work amyotrophic lateral sclerosis therapy brain tissue cohort design detection platform diagnostic assay effective therapy end stage disease frontotemporal lobar dementia amyotrophic lateral sclerosis gene therapy hepatoma-derived growth factor human disease insight limbic-predominant age-related TDP-43 encephalopathy mouse model mutant neoantigens neuropathology novel novel diagnostics prognostic prognostic assays protein TDP-43 sporadic amyotrophic lateral sclerosis stathmin therapeutic development therapeutic gene therapy design treatment strategy vector

项目摘要

Amyotrophic Lateral Sclerosis (ALS), a fatal adult onset motor neuron disease characterized by selective loss of upper and lower motor neurons, and Fronto-Temporal Dementia (FTD), a common form of dementia characterized by a progressive deterioration in behaviour, personality and/or language, share a common disease spectrum. The neuropathology involving Transactivation response element DNA-binding protein 43 (TDP-43) occurs in nearly all cases of ALS and large proportion of FTD, neurodegenerative diseases currently without effective therapy. The overarching goals of this proposal are to clarify disease mechanism, determine a therapeutic window for a novel AAV9 gene therapy, and develop a prognostic test for ALS. By developing monoclonal antibodies designed to recognize cryptic exon encode peptides, we show that loss of TDP-43 splicing repression occurs in pre-symptomatic C9ORF72 patients. This novel finding would support the idea that loss of TDP-43 function occurs during early stage of disease. In this application, we will establish this important mechanistic insight. We hypothesize that it would be possible to develop a prognostic test for prodromal phase of ALS, a critical unmet need in the field relevant for recruitment of patients at their earliest stage of disease and for monitoring target engagement in clinical trials. Finally, emerging evidence support the idea that loss of TDP- 43 splicing repression impact on many critical pathways. In contrast to targeting each of these pathways for ALS, we hypothesize that by targeting the mechanism of TDP-43 splicing repression, it may be possible to provide benefit to patients if such therapeutic strategy can be delivered during early disease which can be determined using this new diagnostic assay of TDP-43 “cryptic” peptide. As we showed previously that our AAV9-CTR has the potential to complement the loss of TDP-43 function in ALS, we hypothesize that a window of opportunity for this gene therapy can be defined in our mouse model lacking TDP-43 in spinal motor neurons. Together, results from our proposed studies will have important implications for understanding disease mechanism, validating therapeutic strategy and developing a prognostic test for the prodromal phase of ALS.

肌萎缩性侧索硬化症（ALS）是一种致命的成人发病运动神经元疾病，其特征是选择性的