Immunotherapies for RAN protein diseases

项目摘要 重复扩增突变导致50多种神经退行性疾病，包括亨廷顿病 (HD)和C9 orf 72肌萎缩侧索硬化症。尽管有大量的研究，但没有有效的治疗方法， 任何一种疾病重复扩增突变通常是双向转录的， 相关的非AUG（RAN）预防措施1。这一过程导致扩增的RNA被翻译成有毒的RNA。 RAN蛋白跨越所有阅读框架，而不需要AUG或AUG样起始密码子2。因为 在每个阅读框中都可以翻译有义和反义扩增RNA， 由单一突变产生。据报道，RAN蛋白在受疾病影响的组织中积累 11种扩展性疾病1，3，4例，包括亨廷顿病（HD）5例和脊髓小脑共济失调型 86，由CAG·CTG扩增突变引起; C9 orf 72，由G4 C2·G2 C4 扩展7 -9.有强有力的证据表明，RAN蛋白是有毒的，并有助于越来越多的重复- 扩张障碍，可能是一个有吸引力的治疗目标。C9-ALS BAC的强临床前数据 转基因小鼠表明，被动免疫疗法减少了RAN蛋白，改善了行为，增加了 长寿和改善的神经病理学表型，包括C9-BAC转基因小鼠中的运动神经元存活 老鼠10.虽然有前途，但被动免疫疗法有许多缺点，包括价格昂贵 产生这些抗体，患者必须接受频繁的注射。这个问题的核心假设是 一项建议是，针对RAN蛋白的疫苗接种将是引发有益免疫的有效策略， 在C9 orf 72 ALS和HD小鼠中响应和减轻疾病。我建议通过确定是否 基于RNA的脂质体疫苗可以引发有益的免疫应答，其降低RAN蛋白水平， 在C9-ALS和HD小鼠模型中改善疾病。

Project Summary Repeat expansion mutations cause more than 50 neurodegenerative diseases, including Huntington 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) translation1. 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 codons2. 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 diseases1,3,4, including Huntington’s disease (HD)5 and spinocerebellar ataxia type 86 which are caused by CAG•CTG expansion mutations and C9orf72 which is caused by a G4C2•G2C4 expansion7-9. 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 mice10. While promising, passive immunotherapy comes with many disadvantages including that it is expensive 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.