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.

Biomedicines

Multiplexing AAV Serotype-Specific Neutralizing Antibodies in Preclinical Animal Models and Humans.

Article

Author: Brantly, Mark L. ; Brantly, Mark L ; Kuoch, Hisae ; Krotova, Karina ; Aslanidi, George ; Graham, Melanie L.

The accurate assessment of AAV-specific pre-existing humoral immunity due to natural viral infection is critical for the efficient use of clinical gene therapy. The method described in the present study applies equivalent infection conditions to each AAV serotype (AAV1, AAV2, AAV3, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, and AAVAnc80L65). In the current study, we validated the assay by assessing AAV-neutralizing antibody titers in a limited cohort of random human donors and well-established preclinical large animal models, including dogs and non-human primates (NHPs). We achieved a rapid and accurate evaluation of neutralizing titers for each individual subject that can be used for clinical enrollment based on specific AAV serotypes and individualized selection of the most suitable AAV serotype for each specific patient.

Nature Communications

Enhancing gene transfer to renal tubules and podocytes by context-dependent selection of AAV capsids

Article

Author: Sairavi, Anusha ; Li, Lena ; Adachi, Kei ; Nakai, Hiroyuki ; Luo, Shuhua ; Hakui, Hideyuki ; Galbraith-Liss, Mia S ; Das, Ranjan ; Rajagopal, Pratheppa ; Furusho, Taisuke ; Dissen, Gregory A ; Yamada, Kentaro ; Horikawa, Masahiro ; Andeen, Nicole

AAV vectors show promise for gene therapy; however, kidney gene transfer remains challenging. Here we conduct a barcode-seq-based comparison of 47 AAV capsids administered through different routes in mice, followed by individual validation. We find that local delivery of AAV-KP1, but not AAV9, via the renal vein or pelvis effectively transduces proximal tubules with minimal off-target liver transduction, while systemic AAV9, but not AAV-KP1, enhances proximal tubule and podocyte transduction in chronic kidney disease. We demonstrate that these contrasting observations are partly due to differences in their pharmacokinetics. Importantly, we show that renal pelvis injection overcomes pre-existing immunity, leading to robust and exclusive proximal tubule transduction, in non-human primates (NHPs). In addition, we highlight drastic differences in renal transduction profiles between mice and NHPs. Thus, this study provides mechanistic insights and underscores importance of context-dependent selection of AAV capsids to overcome challenges in gene delivery to the kidney.

100 Deals associated with AAV9–based gene therapy(Virovek/Sanofi)

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Indication	Highest Phase	Country/Location	Organization	Date
Niemann-Pick Disease, Type A	Preclinical	US	Sanofi	21 Aug 2019
Niemann-Pick Disease, Type A	Preclinical	US	Virovek, Inc.	21 Aug 2019

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