权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结