Journal
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
Volume 23, Issue -, Pages 390-405Publisher
CELL PRESS
DOI: 10.1016/j.omtm.2021.10.001
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Funding
- Alzheimer Society Research Program [19-10]
- Carlsberg Internationalisation Fellowship [CF20-0379]
- Canada Research Chairs Program
- Weston Brain Institute
- Canadian Institutes of Health Research [137064, 166184, 168906, 154272]
- National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health [RO1EB003268]
- Temerty Chair in Focused Ultrasound Research
- Weston Brain Institute [TR160014]
- FDC Foundation
- WB Family Foundation
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Efficient gene delivery to the brain using new technologies could provide potential treatments for Alzheimer's disease, although immunological responses will need to be carefully considered.
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.
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