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Exosome-mediated Delivery of Hydrophobically Modified siRNA for Huntingtin mRNA Silencing.


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.

SUBMITTER: Didiot MC 

PROVIDER: S-EPMC5112038 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Exosome-mediated Delivery of Hydrophobically Modified siRNA for Huntingtin mRNA Silencing.

Didiot Marie-Cécile MC   Hall Lauren M LM   Coles Andrew H AH   Haraszti Reka A RA   Godinho Bruno Mdc BM   Chase Kathryn K   Sapp Ellen E   Ly Socheata S   Alterman Julia F JF   Hassler Matthew R MR   Echeverria Dimas D   Raj Lakshmi L   Morrissey David V DV   DiFiglia Marian M   Aronin Neil N   Khvorova Anastasia A  

Molecular therapy : the journal of the American Society of Gene Therapy 20160627 10


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-incub  ...[more]

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