Rationally Engineered AAV Capsids Improve Transduction and Volumetric Spread in the CNS
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 relat...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-09-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S216225311730197X |
| _version_ | 1818109585072848896 |
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| author | Nicholas M. Kanaan Rhyomi C. Sellnow Sanford L. Boye Ben Coberly Antonette Bennett Mavis Agbandje-McKenna Caryl E. Sortwell William W. Hauswirth Shannon E. Boye Fredric P. Manfredsson |
| author_facet | Nicholas M. Kanaan Rhyomi C. Sellnow Sanford L. Boye Ben Coberly Antonette Bennett Mavis Agbandje-McKenna Caryl E. Sortwell William W. Hauswirth Shannon E. Boye Fredric P. Manfredsson |
| author_sort | Nicholas M. Kanaan |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-12-11T02:33:35Z |
| format | Article |
| id | doaj.art-6d0d371fda0549eea1c15d7cb44b1c23 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-11T02:33:35Z |
| publishDate | 2017-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-6d0d371fda0549eea1c15d7cb44b1c232022-12-22T01:23:47ZengElsevierMolecular Therapy: Nucleic Acids2162-25312017-09-018184197Rationally Engineered AAV Capsids Improve Transduction and Volumetric Spread in the CNSNicholas M. Kanaan0Rhyomi C. Sellnow1Sanford L. Boye2Ben Coberly3Antonette Bennett4Mavis Agbandje-McKenna5Caryl E. Sortwell6William W. Hauswirth7Shannon E. Boye8Fredric P. Manfredsson9Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Mercy Health Saint Mary’s, Grand Rapids, MI 49503, USADepartment of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI 49503, USADepartment of Ophthalmology, University of Florida, Gainesville, FL 32610, USADepartment of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Neuroscience Program, Michigan State University, East Lansing, MI 48825, USADepartment of Biochemistry and Molecular Biology, The McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Biochemistry and Molecular Biology, The McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Mercy Health Saint Mary’s, Grand Rapids, MI 49503, USADepartment of Ophthalmology, University of Florida, Gainesville, FL 32610, USADepartment of Ophthalmology, University of Florida, Gainesville, FL 32610, USADepartment of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Mercy Health Saint Mary’s, Grand Rapids, MI 49503, USA; Corresponding author: Fredric P. Manfredsson, Department of Translational Science and Molecular Medicine, Michigan State University, 333 Bostwick Avenue NE, Grand Rapids, MI 49503-2532, USA.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, mutanthttp://www.sciencedirect.com/science/article/pii/S216225311730197X |
| spellingShingle | Nicholas M. Kanaan Rhyomi C. Sellnow Sanford L. Boye Ben Coberly Antonette Bennett Mavis Agbandje-McKenna Caryl E. Sortwell William W. Hauswirth Shannon E. Boye Fredric P. Manfredsson Rationally Engineered AAV Capsids Improve Transduction and Volumetric Spread in the CNS Molecular Therapy: Nucleic Acids |
| title | Rationally Engineered AAV Capsids Improve Transduction and Volumetric Spread in the CNS |
| title_full | Rationally Engineered AAV Capsids Improve Transduction and Volumetric Spread in the CNS |
| title_fullStr | Rationally Engineered AAV Capsids Improve Transduction and Volumetric Spread in the CNS |
| title_full_unstemmed | Rationally Engineered AAV Capsids Improve Transduction and Volumetric Spread in the CNS |
| title_short | Rationally Engineered AAV Capsids Improve Transduction and Volumetric Spread in the CNS |
| title_sort | rationally engineered aav capsids improve transduction and volumetric spread in the cns |
| url | http://www.sciencedirect.com/science/article/pii/S216225311730197X |
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