Title

Rationally Engineered AAV Capsids Improve Transduction and Volumetric Spread in the CNS

Authors

Nicholas M. Kanaan, Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Mercy Health Saint Mary's, Grand Rapids, MI 49503, USA.
Rhyomi C. Sellnow, Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI 49503, USA.
Sanford L. Boye, Department of Ophthalmology, University of Florida, Gainesville, FL 32610, USA.
Ben Coberly, Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Neuroscience Program, Michigan State University, East Lansing, MI 48825, USA.
Antonette Bennett, Department of Biochemistry and Molecular Biology, The McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Mavis Agbandje-McKenna, Department of Biochemistry and Molecular Biology, The McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Caryl E. Sortwell, Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Mercy Health Saint Mary's, Grand Rapids, MI 49503, USA.
William W. Hauswirth, Department of Ophthalmology, University of Florida, Gainesville, FL 32610, USA.
Shannon E. Boye, Department of Ophthalmology, University of Florida, Gainesville, FL 32610, USA.
Fredric P. Manfredsson, Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Mercy Health Saint Mary's, Grand Rapids, MI 49503, USA. Electronic address: fredric.manfredsson@hc.msu.edu.

Document Type

Article

Abstract

Adeno-associated virus (AAV) is the most common vector for clinical gene therapy of the CNS. This popularity originates from a high safety record and the longevity of transgene expression in neurons. Nevertheless, clinical efficacy for CNS indications is lacking, and one reason for this is the relatively limited spread and transduction efficacy in large regions of the human brain. Using rationally designed modifications of the capsid, novel AAV capsids have been generated that improve intracellular processing and result in increased transgene expression. Here, we sought to improve AAV-mediated neuronal transduction to minimize the existing limitations of CNS gene therapy. We investigated the efficacy of CNS transduction using a variety of tyrosine and threonine capsid mutants based on AAV2, AAV5, and AAV8 capsids, as well as AAV2 mutants incapable of binding heparan sulfate (HS). We found that mutating several tyrosine residues on the AAV2 capsid significantly enhanced neuronal transduction in the striatum and hippocampus, and the ablation of HS binding also increased the volumetric spread of the vector. Interestingly, the analogous tyrosine substitutions on AAV5 and AAV8 capsids did not improve the efficacy of these serotypes. Our results demonstrate that the efficacy of CNS gene transfer can be significantly improved with minor changes to the AAV capsid and that the effect is serotype specific.

Keywords

AAV, CNS, capsid, mutant

Publication Date

9-15-2017

Publication Title

Molecular therapy. Nucleic acids

ISSN

2162-2531

Volume

8

First Page

184

Last Page

197

PubMed ID

28918020

Digital Object Identifier (DOI)

10.1016/j.omtn.2017.06.011

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