A Rationally Engineered Capsid Variant of AAV9 for Systemic CNS-Directed and Peripheral Tissue-Detargeted Gene Delivery in Neonates

Dan Wang; Shaoyong Li; Dominic J. Gessler; Jun Xie; Li Zhong; Jia Li; Karen Tran; Kim Van Vliet; Lingzhi Ren; Qin Su; Ran He; Jason E. Goetzmann; Terence R. Flotte; Mavis Agbandje-McKenna; Guangping Gao

Molecular Therapy: Methods & Clinical Development (Jun 2018)

A Rationally Engineered Capsid Variant of AAV9 for Systemic CNS-Directed and Peripheral Tissue-Detargeted Gene Delivery in Neonates

Dan Wang,
Shaoyong Li,
Dominic J. Gessler,
Jun Xie,
Li Zhong,
Jia Li,
Karen Tran,
Kim Van Vliet,
Lingzhi Ren,
Qin Su,
Ran He,
Jason E. Goetzmann,
Terence R. Flotte,
Mavis Agbandje-McKenna,
Guangping Gao

Affiliations

Dan Wang: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA
Shaoyong Li: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA
Dominic J. Gessler: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA
Jun Xie: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA
Li Zhong: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA
Jia Li: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA
Karen Tran: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA
Kim Van Vliet: Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32610, USA
Lingzhi Ren: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA
Qin Su: Viral Vector Core, University of Massachusetts Medical School, Worcester, MA 01605, USA
Ran He: Viral Vector Core, University of Massachusetts Medical School, Worcester, MA 01605, USA
Jason E. Goetzmann: New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, LA 70560, USA
Terence R. Flotte: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01605, USA
Mavis Agbandje-McKenna: Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32610, USA; Corresponding author: Mavis Agbandje-McKenna, PhD, Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, University of Florida, Gainesville, FL 32610-0245, USA.
Guangping Gao: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA; Viral Vector Core, University of Massachusetts Medical School, Worcester, MA 01605, USA; West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Corresponding author: Guangping Gao, PhD, Horae Gene Therapy Center, University of Massachusetts Medical School, 368 Plantation Street, AS6-2049, Worcester, MA 01605, USA.

Journal volume & issue: Vol. 9
pp. 234 – 246

Abstract

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Adeno-associated virus (AAV) has provided the gene therapy field with the most powerful in vivo gene delivery vector to realize safe, efficacious, and sustainable therapeutic gene expression. Because many clinically relevant properties of AAV-based vectors are governed by the capsid, much research effort has been devoted to the development of AAV capsids for desired features. Here, we combine AAV capsid discovery from nature and rational engineering to report an AAV9 capsid variant, designated as AAV9.HR, which retains AAV9’s capability to traverse the blood-brain barrier and transduce neurons. This variant shows reduced transduction in peripheral tissues when delivered through intravascular (IV) injection into neonatal mice. Therefore, when IV AAV delivery is used to treat CNS diseases, AAV9.HR has the advantage of mitigating potential off-target effects in peripheral tissues compared to AAV9. We also demonstrate that AAV9.HR is suitable for peripheral tissue-detargeted CNS-directed gene therapy in a mouse model of a fatal pediatric leukodystrophy. In light of recent success with profiling diversified natural AAV capsid repertoires and the understanding of AAV capsid sequence-structure-function relationship, such a combinatory approach to AAV capsid development is expected to further improve vector targeting and expand the vector toolbox for therapeutic gene delivery. Keywords: AAV capsid, adeno-associated virus, CNS disease, gene therapy, tissue detargeting

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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