Immunotherapies for RAN protein diseases

项目摘要 重复扩增突变导致包括亨廷顿病在内的50多种神经退行性疾病 (HD)和C9orf72肌萎缩侧索硬化症。尽管进行了密集的研究，但还没有有效的治疗方法 这些疾病中的任何一种。重复扩增突变通常是双向转录的，可以进行重复 关联的非8月(RAN)转换1。这一过程导致扩展RNA被转化为有毒的 Ran蛋白质跨越所有阅读框架，不需要AUG或AUG样的起始密码子2。因为 正义和反义扩展RNA都可以在每个阅读框架内翻译，最多可以翻译六种有毒蛋白质 是由单一突变产生的。据报道，RAN蛋白在受疾病影响的组织中积聚 在11个扩张性疾病的患者中，1，3，4，包括亨廷顿病(HD)5和脊髓小脑性共济失调类型 86为CAG·CTG扩增突变所致，C9orf72为G4C2·G2C4所致 扩大7-9。有强有力的证据表明，RAN蛋白是有毒的，并导致越来越多的重复- 扩张性疾病，并可能成为一个有吸引力的治疗靶点。C9-ALS BAC中强大的临床前数据 转基因小鼠显示被动免疫治疗减少了RAN蛋白，改善了行为，增加了 C9-BAC转基因动物的寿命和包括运动神经元存活在内的神经病理表型的改善 MICE 10.虽然被动免疫疗法前景看好，但它也有许多缺点，包括费用昂贵 以产生这些抗体，患者必须频繁注射。这一点的中心假设是 建议说，接种RAN蛋白疫苗将是一种有效的策略，以获得有益的免疫。 C9orf72 ALS和HD小鼠的反应和减轻疾病。我建议通过以下方法来检验这个假设： 基于RNA的脂质体疫苗可以诱导有益的免疫反应，降低RAN蛋白水平和 改善C9-ALS和HD小鼠模型的疾病。

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.