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Exosomes as therapeutic delivery vehicles

Delivery represents a significant barrier to the clinical advancement of oligonucleotide therapeutics for the treatment of neurological disorders such as Huntington’s disease. The focus of this collaborative project with the labs of Neil Aronin and Marian DiFiglia is to explore if exosomes can be used as vehicles for efficient and targeted delivery of therapeutic oligonucleotides.

Exosomes have potential to be oligonucleotide delivery vehicles; however robust and scalable methods for loading therapeutic cargo into exosomes are lacking. We have developed methods for the efficient loading of exosomes with therapeutic oligonucleotides, and we have demonstrated that hydrophobically modified siRNAs (hsiRNAs) efficiently load into exosomes upon simple co-incubation without altering vesicle size distribution or intactness. Exosomes loaded with hsiRNA targeting Huntingtin mRNA are efficiently taken up by mouse primary cortical neurons and promote dose-dependent silencing of Htt mRNA. Unilateral infusion of hsiRNA-loaded exosomes into mouse striatum results in bilateral distribution of hsiRNA, promoting the silencing of Huntingtin mRNA. Thus, the packaging of hydrophobically modified oligonucleotides into exosomes represents a key advance in the delivery of therapeutic oligonucleotides. The broad distribution and efficacy of hsiRNA-loaded exosomes delivered to brain is expected to improve the development of advanced therapies for treatment of Huntington’s disease and other neurodegenerative disorders.