Researchers deliver siRNA in exosomes to fight Huntington’s disease

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, University of Massachusetts Medical School researchers 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.

Efficient loading of exosomes with hsiRNAs


(a) hsiRNAHTT schematic and PyMOL model. (b) Flowchart of exosome loading procedure: co-incubation of Cy3-hsiRNA and exosomes results in Cy3-hsiRNA-loaded exosomes that pellet by ultracentrifugation. (c) Bar graphs showing the percent of Cy3-hsiRNA or Cy3-hsiRNA-exosomes in the pellet (black) and supernatant (white) after ultracentrifugation (n = 3; mean ± SD). (d) hsiRNA loading does not affect exosome size distribution (nonloaded exosomes, solid line; hsiRNA-loaded exosomes, dashed line). (e) Electron microscopy of exosomes in the absence (left) or presence (right) of hsiRNA. Exosomes remain intact when loaded with hsiRNA (scale bar = 100nm). hsiRNA, hydrophobically modified small interfering RNA.

Didiot MC, Hall LM, Coles AH, Haraszti RA, Godinho BM, Chase K, Sapp E, Ly S, Alterman JF, Hassler MR, Echeverria D, Raj L, Morrissey DV, DiFiglia M, Aronin N, Khvorova A. (2016) Exosome-mediated Delivery of Hydrophobically Modified siRNA for Huntingtin mRNA Silencing. Mol Ther [Epub ahead of print]. [abstract]

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