Delivery of genes to the brain and spinal cord across the blood-brain barrier (BBB) has not yet been achieved. Here we show that adeno-associated virus (AAV) 9 injected intravenously bypasses the BBB and efficiently targets cells of the central nervous system (CNS). Injection of AAV9-GFP into neonatal mice through the facial vein results in extensive transduction of dorsal root ganglia and motor neurons throughout the spinal cord and widespread transduction of neurons throughout the brain, including the neocortex, hippocampus and cerebellum. In adult mice, tail vein injection of AAV9-GFP leads to robust transduction of astrocytes throughout the entire CNS, with limited neuronal transduction. This approach may enable the development of gene therapies for a range of neurodegenerative diseases, such as spinal muscular atrophy, through targeting of motor neurons, and amyotrophic lateral sclerosis, through targeting of astrocytes. It may also be useful for rapid postnatal genetic manipulations in basic neuroscience studies.
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This work was supported by National Institutes of Health (NIH)/National Eye Institute (NEI) R21EY018491, NIH/National Institute of Neurological Disorders and Stroke (NINDS) R21NS064328, Project A.L.S. and The Muscular Dystrophy Association. We kindly thank Jeff Rothstein (Johns Hopkins University) for the EAAT2 antibody, Terri Shaffer (Nationwide Children's Hospital) for expertise in mouse tail vein injections, Michele Basso (Ohio State University) and Megan Detloff (Ohio State University) for stereology usage and advice and Phillip Popovich (Ohio State University) and Kristina Kigerl (Ohio State University) for expertise in microglial detection.
A.H. and C.M.C. are employees who receive compensation including salary benefits from Special Pathology Services, Charles River, Preclinical Services Nevada, Reno, Nevada 89511, USA.
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Foust, K., Nurre, E., Montgomery, C. et al. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol 27, 59–65 (2009). https://doi.org/10.1038/nbt.1515
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