Selection of an Efficient AAV Vector for Robust CNS Transgene Expression

Killian S. Hanlon; Jonah C. Meltzer; Tetyana Buzhdygan; Ming J. Cheng; Miguel Sena-Esteves; Rachel E. Bennett; Timothy P. Sullivan; Roshanak Razmpour; Yi Gong; Carrie Ng; Josette Nammour; Daniela Maiz; Simon Dujardin; Servio H. Ramirez; Eloise Hudry; Casey A. Maguire

Molecular Therapy: Methods & Clinical Development (Dec 2019)

Selection of an Efficient AAV Vector for Robust CNS Transgene Expression

Killian S. Hanlon,
Jonah C. Meltzer,
Tetyana Buzhdygan,
Ming J. Cheng,
Miguel Sena-Esteves,
Rachel E. Bennett,
Timothy P. Sullivan,
Roshanak Razmpour,
Yi Gong,
Carrie Ng,
Josette Nammour,
Daniela Maiz,
Simon Dujardin,
Servio H. Ramirez,
Eloise Hudry,
Casey A. Maguire

Affiliations

Killian S. Hanlon: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129; Harvard Medical School, Boston, MA 02115, USA
Jonah C. Meltzer: Harvard Medical School, Boston, MA 02115, USA; Alzheimer’s Disease Research Laboratory, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA
Tetyana Buzhdygan: Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Shriners Hospital’s Pediatric Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
Ming J. Cheng: Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129; Harvard Medical School, Boston, MA 02115, USA
Miguel Sena-Esteves: University of Massachusetts Medical School, Worcester, MA 01655, USA
Rachel E. Bennett: Harvard Medical School, Boston, MA 02115, USA; Alzheimer’s Disease Research Laboratory, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA
Timothy P. Sullivan: Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Shriners Hospital’s Pediatric Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
Roshanak Razmpour: Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Shriners Hospital’s Pediatric Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
Yi Gong: Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129; Harvard Medical School, Boston, MA 02115, USA
Carrie Ng: Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129; Harvard Medical School, Boston, MA 02115, USA
Josette Nammour: Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129; Harvard Medical School, Boston, MA 02115, USA
Daniela Maiz: Harvard Medical School, Boston, MA 02115, USA; Alzheimer’s Disease Research Laboratory, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA
Simon Dujardin: Harvard Medical School, Boston, MA 02115, USA; Alzheimer’s Disease Research Laboratory, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA
Servio H. Ramirez: Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Shriners Hospital’s Pediatric Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
Eloise Hudry: Harvard Medical School, Boston, MA 02115, USA; Alzheimer’s Disease Research Laboratory, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA; Corresponding author: Eloise Hudry, Alzheimer’s Disease Research Laboratory, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Casey A. Maguire: Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129; Harvard Medical School, Boston, MA 02115, USA; Corresponding author: Casey A. Maguire, Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129.

Journal volume & issue: Vol. 15
pp. 320 – 332

Abstract

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Adeno-associated virus (AAV) capsid libraries have generated improved transgene delivery vectors. We designed an AAV library construct, iTransduce, that combines a peptide library on the AAV9 capsid with a Cre cassette to enable sensitive detection of transgene expression. After only two selection rounds of the library delivered intravenously in transgenic mice carrying a Cre-inducible fluorescent protein, we flow sorted fluorescent cells from brain, and DNA sequencing revealed two dominant capsids. One of the capsids, termed AAV-F, mediated transgene expression in the brain cortex more than 65-fold (astrocytes) and 171-fold (neurons) higher than the parental AAV9. High transduction efficiency was sex-independent and sustained in two mouse strains (C57BL/6 and BALB/c), making it a highly useful capsid for CNS transduction of mice. Future work in large animal models will test the translation potential of AAV-F. Keywords: adeno-associated virus vector, AAV vector, gene therapy, gene delivery, central nervous system, transduction efficiency, AAV capsid library

Published in Molecular Therapy: Methods & Clinical Development

ISSN: 2329-0501 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Biology (General): Genetics; Science: Biology (General): Cytology
Website: http://www.cell.com/molecular-therapy-family/methods/latest-content

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