Immunotherapies for RAN protein diseases

RAN 蛋白疾病的免疫疗法

基本信息

批准号：
10741424
负责人：
Monica Banez-Coronel
金额：
$ 2.62万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10741424
关键词：
Affect Amyotrophic Lateral Sclerosis Antibodies Antibody Affinity Antibody Formation Antibody Response Autopsy Bacterial Artificial Chromosomes Behavior Brain C9ALS C9ORF72 Chronic Disease Clinical Trials Codon Nucleotides Combined Vaccines Data Dipeptides Disadvantaged Disease Genetic Transcription Human Huntington Disease Immune response Immunotherapy Individual Initiator Codon Injections Lead Liposomes Longevity Measures Motor Neurons Mus Mutation Myotonic Dystrophy Neurodegenerative Disorders Passive Immunotherapy Patients Peptides Phenotype Poly A Prevention approach Process Production Proteins RNA RNA vaccine Reading Frames Reporting Research Spinocerebellar Ataxia Type 5 Spinocerebellar Ataxias T cell response Testing Tissues Transcript Transgenic Mice Translating Translations Vaccination Vaccine Therapy Vaccines behavioral phenotyping cohort cost disease phenotype effective therapy frontotemporal lobar dementia amyotrophic lateral sclerosis immunogenicity improved in vivo molecular phenotype mouse model neuronal survival neuropathology novel polyglutamine pre-clinical prevent protein aggregation sporadic amyotrophic lateral sclerosis therapeutic target vaccine candidate vaccine response vaccine-induced antibodies

项目摘要

Project Summary Repeat expansion mutations cause more than 50 neurodegenerative diseases, including Huntington’s disease (HD) and C9orf72 amyotrophic lateral sclerosis. Despite intense research, there are no effective treatments for any of these disorders. Repeat expansion mutations are often bidirectionally transcribed and can undergo repeat associated non-AUG (RAN) translation (1). This process results in the expansion RNAs being translated into toxic RAN proteins across all reading frames without the requirement for AUG, or AUG-like initiation codons (2). Because both sense and antisense expansion RNAs can be translated in each reading frame, up to six toxic proteins can be produced from a single mutation. RAN proteins have been reported to accumulate in disease- affected tissues of patients for 11 expansion diseases (1, 3, 4), including Huntington’s disease (HD) (5) and spinocerebellar ataxia type 8 (6) which are caused by CAG•CTG expansion mutations and C9orf72 which is caused by a GGGGCC•GGCCCC expansion (7-9). There is strong evidence that RAN proteins are toxic and contribute to a growing number of repeat-expansion disorders and could be an attractive therapeutic target. Strong preclinical data in C9-ALS BAC transgenic mice show that passive immunotherapy reduced RAN proteins, improved behavior, increased longevity, and improved neuropathological phenotypes including motor neuronal survival in C9-BAC transgenic mice (10). While promising, passive immunotherapy comes with many disadvantages including the expense to produce these antibodies and that patients must receive frequent injections. The central hypothesis of this proposal is that vaccination against RAN proteins will be an effective strategy to elicit a beneficial immune response and mitigate disease in C9orf72 ALS and HD mice. I propose to test this hypothesis by determining if RNA-based liposome vaccines can elicit beneficial immune responses that reduce RAN protein levels and improve disease in mouse models of C9-ALS and HD.

项目概要重复扩增突变会导致 50 多种神经退行性疾病，包括亨廷顿病 (HD) 和 C9orf72 肌萎缩侧索硬化症尽管进行了大量研究，但尚无有效的治疗方法。任何这些疾病的重复扩增突变通常是双向转录的并且可以经历重复。相关的非 AUG (RAN) 翻译 (1) 该过程导致扩展 RNA 被翻译成。跨所有阅读框的有毒 RAN 蛋白，无需 AUG 或 AUG 样起始密码子 (2)。因为有义和反义扩展 RNA 都可以在每个阅读框中翻译，因此最多有 6 个有毒物质据报道，RAN 蛋白可以通过单一突变产生，并在疾病中积累。 11 种扩张性疾病 (1, 3, 4) 患者受影响的组织，包括亨廷顿病 (HD) (5) 和脊髓小脑性共济失调 8 型 (6)，由 CAG•CTG 扩展突变和 C9orf72 引起，C9orf72 是由 GGGGCC•GGCCCC 扩展引起 (7-9) 有强有力的证据表明 RAN 蛋白具有毒性和毒性。导致越来越多的重复扩增疾病，并且可能是一个有吸引力的治疗靶点。 C9-ALS BAC 转基因小鼠的强有力的临床前数据表明，被动免疫疗法降低了 RAN 蛋白质，改善行为，延长寿命，改善神经病理表型，包括运动 C9-BAC 转基因小鼠的神经元存活率虽然有希望，但被动免疫疗法有很多好处。缺点包括生产这些抗体的费用以及患者必须经常接受该提案的中心假设是针对 RAN 蛋白的疫苗接种将是一种有效的方法。我建议采用一种策略来引发有益的免疫反应并减轻 C9orf72 ALS 和 HD 小鼠的疾病。通过确定基于 RNA 的脂质体疫苗是否可以引发有益的免疫反应来检验这一假设降低 C9-ALS 和 HD 小鼠模型中的 RAN 蛋白水平并改善疾病。