title: 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.
authors: RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Marie-Cécile
authors: MC
authors: Didiot
authors: RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Lauren M
authors: LM
authors: Hall
authors: RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Andrew H
authors: AH
authors: Coles
authors: RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Reka A
authors: RA
authors: Haraszti
authors: RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Bruno Mdc
authors: BM
authors: Godinho
authors: RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Kathryn
authors: K
authors: Chase
authors: Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors: Ellen
authors: E
authors: Sapp
authors: RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Socheata
authors: S
authors: Ly
authors: RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Julia F
authors: JF
authors: Alterman
authors: RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Matthew R
authors: MR
authors: Hassler
authors: RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Dimas
authors: D
authors: Echeverria
authors: Novartis Institutes for Biomedical Research Inc., Cambridge, Massachusetts, USA.
authors: Lakshmi
authors: L
authors: Raj
authors: Novartis Institutes for Biomedical Research Inc., Cambridge, Massachusetts, USA.
authors: David V
authors: DV
authors: Morrissey
authors: Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors: Marian
authors: M
authors: DiFiglia
authors: RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Neil
authors: N
authors: Aronin
authors: RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Anastasia
authors: A
authors: Khvorova
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D055354:Exosomes / Q000235:genetics*; D005786:Gene Expression Regulation; D020868:Gene Silencing; D015316:Genetic Therapy; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics* / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D034741:RNA, Small Interfering