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Targeted immunotherapy for amyotrophic lateral sclerosis and frontotemporal dementia

肌萎缩侧索硬化症和额颞叶痴呆的靶向免疫治疗

基本信息

批准号：
10759808
负责人：
JAMES W LARRICK
金额：
$ 30万
依托单位：
PANORAMA RESEARCH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10759808
关键词：
Active Immunization Affect Affinity Antibodies Antibody Therapy Antibody titer measurement Antisense Oligonucleotides Attenuated Behavioral Biodistribution Blocking Antibodies Brain C9ORF72 Cachexia Cells Cessation of life Data Defect Denervation Development Dipeptides Disease Dominant-Negative Mutation Drug Kinetics Elements Endosomes Engineering Frontotemporal Dementia Genes Genetic Goals Human Human Pathology Immunotherapy Impairment In Vitro Lead Letters Link Memory Microglia Modeling Monoclonal Antibodies Motor Mus Mutation N-glycylalanine Nerve Degeneration Neurodegenerative Disorders Neurons Pathogenicity Pathology Pathway interactions Patients Phase Plasma Population Preparation Prevention Proteasome Inhibition Proteins Rodent Model Series TANK-binding kinase 1 TDP-43 aggregation Time Toxic effect Toxicology Translations Vaccination Validation assay development blood-brain barrier crossing design effective therapy frontotemporal lobar dementia amyotrophic lateral sclerosis human monoclonal antibodies improved in vitro Assay motor deficit mouse model multicatalytic endopeptidase complex murine antibody neuron loss novel therapeutics phase 1 study pre-clinical protein TDP-43 protein kinase R success targeted treatment trafficking uptake

项目摘要

Targeted immunotherapy for amyotrophic lateral sclerosis and frontotemporal dementia Abstract Frontotemporal dementias (FTD) and amyotrophic lateral sclerosis (ALS) are progressive and fatal neurodegenerative diseases. A hexanucleotide repeat expansion in C9orf72 accounts for >10% of all cases. Non-AUG dependent translation of expanded repeats results in accumulation of several dipeptide repeat (DPR) proteins, of which poly-GA appears central to the pathology of C9orf72 disease. Aggregation of poly-GA inhibits the proteasome and leads to TDP-43 aggregation. Despite widespread poly-GA expression in C9orf72 mouse models, specific disease-relevant neuron populations are especially sensitive to poly-GA toxicity. Antisense oligonucleotides directed to C9orf72 are effective in mice, as is a dominant negative protein kinase R (PKR) that attenuates poly-GA accumulation. Preliminary data indicate that active vaccination induces high antibody titers and nearly complete prevention of motor deficits and microglia activation in mice, suggesting poly-GA as a feasible target to treat C9orf72 FTD/ALS. Poly-GA antibodies block aggregation and spreading of poly-GA and attenuate downstream TDP-43 pathology in vitro, and improve motor and behavioral deficits in mouse models. These data suggest that immunotherapy is currently the best approach to reduce toxicity of aggregates that are found even in pre-symptomatic carriers. Our team has identified potent murine antibodies that demonstrate activity in a C9orf72 mouse model. During this Phase 1 study, we propose to humanize our lead anti-GA antibody and conduct preclinical validation of anti-GA antibody therapy in several disease-relevant mouse models.

肌萎缩侧索硬化和额颞叶的靶向免疫治疗痴呆摘要额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS）是进行性和致命的神经退行性疾病C9 orf 72中的六核苷酸重复扩增占所有病例的>10%。扩增重复序列的非AUG依赖性翻译导致几个二肽重复序列（DPR）的积累蛋白质，其中poly-GA似乎是C9 orf 72疾病病理学的核心。聚-GA的聚集抑制蛋白酶体并导致TDP-43聚集。尽管在C9 orf 72小鼠中广泛表达聚-GA，模型中，特定疾病相关的神经元群体对聚GA毒性特别敏感。反义针对C9 orf 72的寡核苷酸在小鼠中是有效的，减弱聚-GA积累。初步数据表明，主动接种可诱导高抗体滴度并且几乎完全预防小鼠的运动缺陷和小胶质细胞活化，这表明聚-GA是一种有效的治疗方法。治疗C9 orf 72 FTD/ALS的可行靶点。聚-GA抗体阻断聚-GA的聚集和扩散，在体外减弱下游TDP-43病理学，并改善小鼠模型中的运动和行为缺陷。这些数据表明，免疫疗法是目前降低聚集体毒性的最佳方法，甚至在症状前的携带者中也能发现。我们的团队已经鉴定出了有效的鼠抗体，在C9 orf 72小鼠模型中的活性。在第一阶段的研究中，我们建议将我们的抗GA抗体人源化并在几种疾病相关小鼠模型中进行抗GA抗体治疗的临床前验证。