RNA Therapeutics Institute; Program in Molecular Medicine; Department of Medicine
Biochemistry, Biophysics, and Structural Biology | Cell and Developmental Biology | Genetics and Genomics | Molecular Biology | Neuroscience and Neurobiology | Therapeutics
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.
siRNA, Huntingtin, mRNA, messenger RNA, UMCCTS funding
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Copyright © 2016 American Society of Gene and Cell Therapy. Under a Creative Commons license.
DOI of Published Version
Mol Ther. 2016 Oct;24(10):1836-1847. doi: 10.1038/mt.2016.126. Epub 2016 Jun 27. Link to article on publisher's site
Molecular therapy : the journal of the American Society of Gene Therapy
Didiot MC, Hall LM, Coles AH, Haraszti RA, Godinho B, Chase KO, Ly S, Alterman JF, Hassler MR, Echeverria D, Aronin N, Khvorova A. (2016). Exosome-mediated Delivery of Hydrophobically Modified siRNA for Huntingtin mRNA Silencing. RNA Therapeutics Institute Publications. https://doi.org/10.1038/mt.2016.126. Retrieved from https://escholarship.umassmed.edu/rti_pubs/12
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