The engineered AAV2-HBKO promotes non-invasive gene delivery to large brain regions beyond ultrasound targeted sites

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Rikke Hahn Kofoed
  • Kate Noseworthy, Sunnybrook Research Institute, University of Toronto Faculty of Medicine
  • ,
  • Kathleen Wu, Sunnybrook Research Institute
  • ,
  • Shuruthisai Sivadas, Sunnybrook Research Institute
  • ,
  • Lisa Stanek, Sanofi S.A.
  • ,
  • Bradford Elmer, Sanofi S.A.
  • ,
  • Kullervo Hynynen, Sunnybrook Research Institute, University of Toronto Faculty of Medicine
  • ,
  • Lamya S. Shihabuddin, Sanofi S.A.
  • ,
  • Isabelle Aubert, Sunnybrook Research Institute, University of Toronto Faculty of Medicine

Magnetic resonance imaging-guided focused ultrasound combined with microbubbles injected in the bloodstream (MRIgFUS) temporarily increases the permeability of the blood-brain barrier (BBB), which facilitates the entry of intravenously administered adeno-associated viruses (AAVs) from the blood to targeted brain areas. To date, the properties of the AAVs used for MRIgFUS delivery resulted in cell transduction limited to MRIgFUS-targeted sites. Considering future clinical applications, strategies are needed to deliver genes to multiple locations and large brain volumes while creating minimal BBB modulation. Here we combine MRIgFUS with a vector that has enhanced biodistribution following brain entry, AAV2-HBKO, to mediate broad gene delivery to targeted brain regions at levels with potential therapeutic relevance. Expression of a reporter gene was achieved in 13% and 21% of all neurons present in the striatum and thalamus, respectively, while targeting only 28% of the brain regions with MRIgFUS. Compared with AAV9, MRIgFUS-mediated delivery of AAV2-HBKO showed greater diffusion in the brain and a higher percentage of the neurons expressing the transgene. MRIgFUS AAV2-HBKO gene delivery to the brain has the potential to reach levels that are functionally and clinically relevant, and this even when using relatively low intravenous AAV dosages, compared with what is currently used in clinical trials.

Original languageEnglish
JournalMolecular Therapy - Methods and Clinical Development
Pages (from-to)167-184
Number of pages18
Publication statusPublished - 8 Dec 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022 The Author(s)

    Research areas

  • AAV2-HBKO, adeno-associated virus, blood-brain barrier, focused ultrasound, gene delivery, microbubbles

See relations at Aarhus University Citationformats

ID: 311383864