Transgene distribution and immune response after ultrasound delivery of rAAV9 and PHP.B to the brain in a mouse model of amyloidosis

Rikke Hahn Kofoed; Stefan Heinen; Joseph Silburt; Sonam Dubey; Chinaza Lilian Dibia; Miriam Maes; Elizabeth M Simpson; Kullervo Hynynen; Isabelle Aubert

doi:10.1016/j.omtm.2021.10.001

Transgene distribution and immune response after ultrasound delivery of rAAV9 and PHP.B to the brain in a mouse model of amyloidosis

Mol Ther Methods Clin Dev. 2021 Oct 8:23:390-405. doi: 10.1016/j.omtm.2021.10.001. eCollection 2021 Dec 10.

Authors

Rikke Hahn Kofoed^{1

2}, Stefan Heinen^{1

2}, Joseph Silburt^{1

2}, Sonam Dubey^{1

2}, Chinaza Lilian Dibia^{1

2}, Miriam Maes^{1

2}, Elizabeth M Simpson³, Kullervo Hynynen^{4

5}, Isabelle Aubert^{1

2}

Affiliations

¹ Biological Sciences, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada.
² Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
³ Centre for Molecular Medicine and Therapeutics at British Columbia Children's Hospital, Department of Medical Genetics, The University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
⁴ Physical Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada.
⁵ Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5G 1L7, Canada.

Abstract

Efficient disease-modifying treatments for Alzheimer disease, the most common form of dementia, have yet to be established. Gene therapy has the potential to provide the long-term production of therapeutic in the brain following a single administration. However, the blood-brain barrier poses a challenge for gene delivery to the adult brain. We investigated the transduction efficiency and immunological response following non-invasive gene-delivery strategies to the brain of a mouse model of amyloidosis. Two emerging technologies enabling gene delivery across the blood-brain barrier were used to establish the minimal vector dosage required to reach the brain: (1) focused ultrasound combined with intravenous microbubbles, which increases the permeability of the blood-brain barrier at targeted sites and (2) the recombinant adeno-associated virus (rAAV)-based capsid named rAAV-PHP.B. We found that equal intravenous dosages of rAAV9 combined with focused ultrasound, or rAAV-PHP.B, were required for brain gene delivery. In contrast to rAAV9, focused ultrasound did not decrease the rAAV-PHP.B dosage required to transduce brain cells in a mouse model of amyloidosis. The non-invasive rAAV delivery to the brain using rAAV-PHP.B or rAAV9 with focused ultrasound triggered an immune reaction including major histocompatibility complex class II expression, complement system and microglial activation, and T cell infiltration.

Keywords: Alzheimer disease; TgCRND8; adeno-associated virus; blood-brain barrier; focused ultrasound; immune response; machine learning; microbubbles; rAAV-PHP.B.

Grants and funding

R01 EB003268/EB/NIBIB NIH HHS/United States