| Literature DB >> 27506293 |
Marie-Cécile Didiot1,2, Lauren M Hall1,3, Andrew H Coles1,2, Reka A Haraszti1,2, Bruno Mdc Godinho1,2, Kathryn Chase1,3, Ellen Sapp4, Socheata Ly1,2, Julia F Alterman1,2, Matthew R Hassler1,2, Dimas Echeverria1,2, Lakshmi Raj5, David V Morrissey5, Marian DiFiglia4, Neil Aronin1,3, Anastasia Khvorova1,2.
Abstract
Delivery represents a significant barrier to the clinical advancement of oligonucleotide therapeutics for the treatment of neurological disorders, such as Huntington's disease. Small, endogenous vesicles known as exosomes have the potential to act as oligonucleotide delivery vehicles, but robust and scalable methods for loading RNA therapeutic cargo into exosomes are lacking. Here, we show that hydrophobically modified small interfering RNAs (hsiRNAs) efficiently load into exosomes upon co-incubation, without altering vesicle size distribution or integrity. Exosomes loaded with hsiRNAs targeting Huntingtin mRNA were efficiently internalized by mouse primary cortical neurons and promoted dose-dependent silencing of Huntingtin mRNA and protein. Unilateral infusion of hsiRNA-loaded exosomes, but not hsiRNAs alone, into mouse striatum resulted in bilateral oligonucleotide distribution and statistically significant bilateral silencing of up to 35% of Huntingtin mRNA. The broad distribution and efficacy of hsiRNA-loaded exosomes delivered to brain is expected to advance the development of therapies for the treatment of Huntington's disease and other neurodegenerative disorders.Entities:
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Year: 2016 PMID： 27506293 PMCID： PMC5112038 DOI： 10.1038/mt.2016.126
Source DB: PubMed Journal: Mol Ther ISSN： 1525-0016 Impact factor: 11.454