Efficacy of gene delivery to the brain using AAV and ultrasound depends on serotypes and brain areas

Kofoed, Rikke Hahn; Dibia, Chinaza Lilian; Noseworthy, Kate; Xhima, Kristiana; Vacaresse, Nathalie; Hynynen, Kullervo; Aubert, Isabelle

doi:10.1016/j.jconrel.2022.09.048

Cited by 23 publications

(35 citation statements)

References 73 publications

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“…Such somewhat restricted GFP expression despite the large-volume BBB opening (as assessed by both MRI and 18 F-Choline PET imaging) is a crucial point to resolve. In this context, it has recently been reported in rodents that the serotypes of AAV vectors, the extent of LIFU-induced BBB permeability, and the intrinsic properties of the targeted brain tissue influence the efficacy of neuronal transduction via the vectors and the biodistribution and diffusion of transduced neurons ( 36 , 44 ). There are major differences in the degree of vector-induced transgene expression between rodents and primates ( 26 , 27 , 36 ).…”

Section: Discussionmentioning

confidence: 99%

BBB opening with focused ultrasound in nonhuman primates and Parkinson’s disease patients: Targeted AAV vector delivery and PET imaging

et al. 2023

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Intracerebral vector delivery in nonhuman primates has been a major challenge. We report successful blood-brain barrier opening and focal delivery of adeno-associated virus serotype 9 vectors into brain regions involved in Parkinson’s disease using low-intensity focus ultrasound in adult macaque monkeys. Openings were well tolerated with generally no associated abnormal magnetic resonance imaging signals. Neuronal green fluorescent protein expression was observed specifically in regions with confirmed blood-brain barrier opening. Similar blood-brain barrier openings were safely demonstrated in three patients with Parkinson’s disease. In these patients and in one monkey, blood-brain barrier opening was followed by 18 F-Choline uptake in the putamen and midbrain regions based on positron emission tomography. This indicates focal and cellular binding of molecules that otherwise would not enter the brain parenchyma. The less-invasive nature of this methodology could facilitate focal viral vector delivery for gene therapy and might allow early and repeated interventions to treat neurodegenerative disorders.

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Section: Discussionmentioning

confidence: 99%

BBB opening with focused ultrasound in nonhuman primates and Parkinson’s disease patients: Targeted AAV vector delivery and PET imaging

et al. 2023

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“…The method described in the present study is not the only approach to improve upon the traditional method of AAV delivery by insertion of a glass pipette. For example, recent studies have proven that focused ultrasound combined with intravenously injected microbubbles, can deliver systemically administered AAVs to any brain region of interest 7,12 . While this approach could be a transformative step for clinical application of gene therapy, BBB disruption and gene transduction occur over a relatively large volume (~0.125-1 mm 3 ), and therefore it is not suitable for micron level precision of AAV delivery and longitudinal imaging of sparsely labelled cells.…”

Section: Discussionmentioning

confidence: 99%

“…While revolutionary, the application of these methods has been slowed by the fact that delivery of the light sensitive cre-recombinase involves the aforementioned BBB permeable AAVs, which can yield capricious expression in some mouse strains or avoid certain cells in vivo 5 . Another recent approach that has generated tremendous excitement is the use of focused ultrasound (FUS) to remotely and transiently disrupt the BBB with microbubbles, in order to deliver AAVs [6][7][8][9] . The benefits of this method is that one can non-invasively deliver AAVs to any brain region of interest.…”

Section: Introductionmentioning

confidence: 99%

Optical opening of the blood brain barrier for targeted and ultra-sparse viral infection of cells in the mouse cortex

Reeson

Boghozian

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et al. 2022

Preprint

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Adeno-associated viruses (AAVs) are used in a wide array of experimental situations for driving expression of biosensors, recombinases and opto/chemo-genetic actuators in the brain. However, conventional approaches for minimally invasive, spatially precise and ultra-sparse AAV mediated transduction of cells during imaging experiments, has remained a significant challenge. Here we show that intravenous injection of commercially available AAVs at different doses, combined with laser based perforation of single cortical capillaries through a cranial widow, allows for ultra-sparse, titrate-able, and micron level precision for delivery of viral vectors with relatively little inflammation or tissue damage. Further, we show the utility of this approach for eliciting sparse expression of GCaMP6, channel-rhodopsin or fluorescent reporters in neurons and astrocytes within specific functional domains in normal and stroke damaged cortex. This technique represents a facile approach for targeted delivery of viral vectors that should assist in the study of cell types and circuits in the cerebral cortex.

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“…This study provides a reliable choice for designing safe and effective gene delivery strategies. 92 Furthermore, Touahri et al have extended this approach to Müller glial cells to stimulate their repair potential in degenerative diseases. 93 In addition, the extensive application of US-responsive materials spurred the development of inorganic-based nanomaterials, which were designed in various shapes and sizes for drug delivery.…”

Section: Carrier-based Drug Deliverymentioning

confidence: 99%

Section: Us-enhanced Cellular Endocytosis Strategies For Biomedical A...mentioning

confidence: 99%

Ultrasound meets the cell membrane: for enhanced endocytosis and drug delivery

et al. 2023

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Efficacy of gene delivery to the brain using AAV and ultrasound depends on serotypes and brain areas

Cited by 23 publications

References 73 publications

BBB opening with focused ultrasound in nonhuman primates and Parkinson’s disease patients: Targeted AAV vector delivery and PET imaging

BBB opening with focused ultrasound in nonhuman primates and Parkinson’s disease patients: Targeted AAV vector delivery and PET imaging

Optical opening of the blood brain barrier for targeted and ultra-sparse viral infection of cells in the mouse cortex

Ultrasound meets the cell membrane: for enhanced endocytosis and drug delivery

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