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Controlling AAV Tropism in the Nervous System with Natural and Engineered Capsids

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Gene Therapy for Neurological Disorders

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1382))

Abstract

More than one hundred naturally occurring variants of adeno-associated virus (AAV) have been identified, and this library has been further expanded by an array of techniques for modification of the viral capsid. AAV capsid variants possess unique antigenic profiles and demonstrate distinct cellular tropisms driven by differences in receptor binding. AAV capsids can be chemically modified to alter tropism, can be produced as hybrid vectors that combine the properties of multiple serotypes, and can carry peptide insertions that introduce novel receptor-binding activity. Furthermore, directed evolution of shuffled genome libraries can identify engineered variants with unique properties, and rational modification of the viral capsid can alter tropism, reduce blockage by neutralizing antibodies, or enhance transduction efficiency. This large number of AAV variants and engineered capsids provides a varied toolkit for gene delivery to the CNS and retina, with specialized vectors available for many applications, but selecting a capsid variant from the array of available vectors can be difficult. This chapter describes the unique properties of a range of AAV variants and engineered capsids, and provides a guide for selecting the appropriate vector for specific applications in the CNS and retina.

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Acknowledgments

The AAV work in our laboratories is supported by NIH grants R01-NS038690, R01-DK063973 and U01-HD079066 to J.H.W. and DP1-OD008267 to L.H.V.; additional support was provided to J.H.W. from the Foerderer Fdn and to L.H.V. from Curing Kids Fund, Foundation for Retina Research, Foundation Fighting Blindness, Research to Prevent Blindness, and Corinne and Wyc Grousbeck. M.J.C. was supported in part by NIH T32-NS007413. L.H.V. is an inventor on patents related to AAV gene therapy ; has served as a consultant; is inventor on technologies licensed to biotechnology and pharmaceutical industry; and is cofounder and consultant to GenSight Biologics.

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Authors and Affiliations

  1. Research Institute of the Children’s Hospital of Philadelphia, 502-G Abramson Pediatric Research Building, 3615 Civic Center Boulevard, Philadelphia, PA, 19104, USA

    Michael J. Castle & John H. Wolfe

  2. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    John H. Wolfe

  3. W.F. Goodman Center for Comparative Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    John H. Wolfe

  4. Department of Neurosciences, University of California-San Diego, La Jolla, CA, 92093, USA

    Michael J. Castle

  5. Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear Hospital, Harvard Medical School, Boston, MA, 02114, USA

    Heikki T. Turunen & Luk H. Vandenberghe

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  1. Michael J. Castle
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  2. Heikki T. Turunen
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  3. Luk H. Vandenberghe
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  4. John H. Wolfe
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Correspondence to John H. Wolfe .

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  1. Translational Science and Molecular Medicine, Michigan State University, College of Human Science, Grand Rapids, Michigan, USA

    Fredric P. Manfredsson

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Castle, M.J., Turunen, H.T., Vandenberghe, L.H., Wolfe, J.H. (2016). Controlling AAV Tropism in the Nervous System with Natural and Engineered Capsids. In: Manfredsson, F. (eds) Gene Therapy for Neurological Disorders. Methods in Molecular Biology, vol 1382. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3271-9_10

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  • DOI: https://doi.org/10.1007/978-1-4939-3271-9_10

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-3270-2

  • Online ISBN: 978-1-4939-3271-9

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