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Brain. 2018 Jul 1;141(7):2014-2031. doi: 10.1093/brain/awy126.

A novel adeno-associated virus capsid with enhanced neurotropism corrects a lysosomal transmembrane enzyme deficiency.

Author information

Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, London, UK.
Stem Cell and Neurotherapies, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK.
Molecular Neuromodulation, Wallenberg Neuroscience Center, Lund University, Lund, Sweden.
Department of Genetics, UCL Institute of Ophthalmology, London, UK.
Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA.
CHU Ste-Justine, University of Montreal, Montreal, Canada.
Centre Hospitalo-Universitaire de Toulouse, Institut Fédératif de Biologie, Laboratoire de Biochimie Métabolique, and Unité Mixte de Recherche (UMR) 1037 Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Toulouse, Toulouse, France.
Manchester Collaborative Centre for Inflammation Research, Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK.
Department of Pediatrics, Powell Gene Therapy Center, University of Florida, Gainesville, FL, USA.
Department of Pharmacology, UCL School of Pharmacy, University College London, London, UK.
Gene Transfer Technology Group, Institute for Women's Health, University College London, London, UK.
Wits/SAMRC Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.


Recombinant adeno-associated viruses (AAVs) are popular in vivo gene transfer vehicles. However, vector doses needed to achieve therapeutic effect are high and some target tissues in the central nervous system remain difficult to transduce. Gene therapy trials using AAV for the treatment of neurological disorders have seldom led to demonstrated clinical efficacy. Important contributing factors are low transduction rates and inefficient distribution of the vector. To overcome these hurdles, a variety of capsid engineering methods have been utilized to generate capsids with improved transduction properties. Here we describe an alternative approach to capsid engineering, which draws on the natural evolution of the virus and aims to yield capsids that are better suited to infect human tissues. We generated an AAV capsid to include amino acids that are conserved among natural AAV2 isolates and tested its biodistribution properties in mice and rats. Intriguingly, this novel variant, AAV-TT, demonstrates strong neurotropism in rodents and displays significantly improved distribution throughout the central nervous system as compared to AAV2. Additionally, sub-retinal injections in mice revealed markedly enhanced transduction of photoreceptor cells when compared to AAV2. Importantly, AAV-TT exceeds the distribution abilities of benchmark neurotropic serotypes AAV9 and AAVrh10 in the central nervous system of mice, and is the only virus, when administered at low dose, that is able to correct the neurological phenotype in a mouse model of mucopolysaccharidosis IIIC, a transmembrane enzyme lysosomal storage disease, which requires delivery to every cell for biochemical correction. These data represent unprecedented correction of a lysosomal transmembrane enzyme deficiency in mice and suggest that AAV-TT-based gene therapies may be suitable for treatment of human neurological diseases such as mucopolysaccharidosis IIIC, which is characterized by global neuropathology.

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