Exosome based therapeutics in Huntington's disease

基于外泌体的亨廷顿病疗法

基本信息

批准号：
9325094
负责人：
NEIL ARONIN
金额：
$ 97.24万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9325094
关键词：
Adolescence Adolescent Adult Affect Age Age-Years Alleles Animal Disease Models Antigens Antisense Oligonucleotides Area Behavior Behavior assessment Blood Blood - brain barrier anatomy Blood Circulation Brain Brain Diseases CAG repeat Caring Catheters Cells Cerebrospinal Fluid Child Cleaved cell Clinical Cognitive Corpus striatum structure Cytoplasm Dependovirus Deposition Development Discipline of Nursing Disease Dose Dyskinetic syndrome Foundations Gene Silencing Genetic Goals Human Huntington Disease Huntington gene Immune Immune response Impaired cognition Infusion procedures Inherited Injectable Injection of therapeutic agent Measurement Measures Memory Mental Depression Messenger RNA Methods MicroRNAs Movement Multivesicular Body Mus Nerve Degeneration Neuroglia Neurons Nurses Parents Pathogenesis Pathway interactions Patients Peripheral Prevention Production Proteins RNA RNA Interference RNA Splicing Risk Secure Series Site Small Interfering RNA Small RNA Source Structure Surface Tail Testing Therapeutic Therapeutic Studies Treatment Efficacy Variant Veins base brain cell combinatorial cost deep sequencing exosome gene product immunogenicity in vivo knock-down microvesicles mouse model mutant neuropathology nonhuman primate prevent public health relevance rabies virus glycoprotein G small hairpin RNA theories uptake

项目摘要

DESCRIPTION (provided by applicant): The goal of this UH2 and UH3 is to study how exosomes can deliver siRNAs across the blood brain barrier to enter neurons and other brain cells. The immediate target is the mutant huntingtin mRNA. Huntington's disease (HD) is caused by an increase in the CAG trinucleotide repeats to � 36 in series; it necessitates years in a high level nursing facility because of neurodegeneration first in striatum and cortex and then to other brain structures. HD patients have cognitive impairment, depression and aberrant movements. Most HD patient present by 30 to 40 years of age; a few have a juvenile onset. A rational treatment is to decrease expression of mutant huntingtin mRNA; this therapeutic can be accomplished in HD mouse models by siRNA, antisense oligonucleotides (ASO) and adeno-associated virus (AAV) with shRNAmir directed against huntingtin mRNA. However, delivery remains a pitfall to practical implementation of the therapeutics. siRNA and ASO require long-term infusion. In non-human primates, ASO administered to spinal fluid does not reach the striatum and spread of siRNA is limited in brain. Although promising, AAV-shRNA requires several injections into brain areas and the shRNAmir is unregulated. A gap in HD therapeutics can be filled by microvesicles normally extruded by cells, exosomes. Exosomes with rabies virus glycoprotein (RVG) on their surface can be injected into the blood, cross the blood brain barrier, and enter neurons and glia. RVG-exosomes can carry siRNA cargo. Delivered into the blood circulation, the exosomes deposit siRNA in neurons to engage in RNA interference. Our purpose is to develop exosomes as a therapeutic in HD. The UH2 examines the ability of RVG-exosomes carrying siRNA against huntingtin mRNA to cross the blood brain barrier to enter neurons. Localization in brain and RNAi dependent knock down will be studied. Hyper-functional siRNAs will be sought. Because exosomes are made from cytoplasm of cells, exosome mRNA, miRNA, and implaced siRNA will be identified by deep sequencing. Immune reactivity and immune-neutralization will be studied, since exosomes have potential antigens, like RVG, and will need to be administrated often. The UH3 further establishes exosome-based therapeutics, by study of reversal or prevention of neuropathology and aberrant movement in HD mouse models. Dosing of exosomes will be secured. A team of experts in HD pathogenesis, siRNA development, RNA identification and measurement, RNAi mechanisms and exosome production and brain delivery will carry out the studies. Harnessing exosomes for brain delivery is expected to form a viable therapeutic to reduce expression of mutant huntingtin in patients with HD. Patients with other genetically- based neurodegeneration will benefit.

描述（通过应用来证明）：UH2和UH3的目的是研究外泌体如何在血液中的神经元和其他脑细胞中删除。 CAG三核苷酸在纹状体和脑结构中首先重复，并在30至40岁的情况下使用大脑的大脑结构。）和与shrnamir的adeno相关病毒（AAV），但是，对mRNA进行了反对的陷阱。对脊柱的施用不受纹状体的限制。血脑屏障，进入神经元和神经元。将在脑部障碍中进行杂交，并研究依赖RNAi的sirnize sirnas。像RVG一样，需要经常进行管理。突变的Huth HD的表达将受益。