Immunotherapies for RAN protein diseases

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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.