In Silico Reconstruction of the Viral Evolutionary Lineage Yields a Potent Gene Therapy Vector

Adeno-associated virus (AAV) vectors have emerged as a gene-delivery platform with demonstrated safety and efficacy in a handful of clinical trials for monogenic disorders. However, limitations of the current generation vectors often prevent broader application of AAV gene therapy. Efforts to engine...

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Main Authors:	Eric Zinn, Simon Pacouret, Vadim Khaychuk, Heikki T. Turunen, Livia S. Carvalho, Eva Andres-Mateos, Samiksha Shah, Rajani Shelke, Anna C. Maurer, Eva Plovie, Ru Xiao, Luk H. Vandenberghe
Format:	Article
Language:	English
Published:	Elsevier 2015-08-01
Series:	Cell Reports
Online Access:	http://www.sciencedirect.com/science/article/pii/S2211124715007597

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spelling	doaj-9941e6a1cc964651b74a08eb30bc49f92020-11-25T01:49:37ZengElsevierCell Reports2211-12472015-08-011261056106810.1016/j.celrep.2015.07.019In Silico Reconstruction of the Viral Evolutionary Lineage Yields a Potent Gene Therapy VectorEric Zinn0Simon Pacouret1Vadim Khaychuk2Heikki T. Turunen3Livia S. Carvalho4Eva Andres-Mateos5Samiksha Shah6Rajani Shelke7Anna C. Maurer8Eva Plovie9Ru Xiao10Luk H. Vandenberghe11Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, 20 Staniford Street, Boston, MA 02114, USAGrousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, 20 Staniford Street, Boston, MA 02114, USAGrousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, 20 Staniford Street, Boston, MA 02114, USAGrousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, 20 Staniford Street, Boston, MA 02114, USAGrousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, 20 Staniford Street, Boston, MA 02114, USAGrousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, 20 Staniford Street, Boston, MA 02114, USAGrousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, 20 Staniford Street, Boston, MA 02114, USAGrousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, 20 Staniford Street, Boston, MA 02114, USAGrousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, 20 Staniford Street, Boston, MA 02114, USAGrousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, 20 Staniford Street, Boston, MA 02114, USAGrousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, 20 Staniford Street, Boston, MA 02114, USAGrousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, 20 Staniford Street, Boston, MA 02114, USAAdeno-associated virus (AAV) vectors have emerged as a gene-delivery platform with demonstrated safety and efficacy in a handful of clinical trials for monogenic disorders. However, limitations of the current generation vectors often prevent broader application of AAV gene therapy. Efforts to engineer AAV vectors have been hampered by a limited understanding of the structure-function relationship of the complex multimeric icosahedral architecture of the particle. To develop additional reagents pertinent to further our insight into AAVs, we inferred evolutionary intermediates of the viral capsid using ancestral sequence reconstruction. In-silico-derived sequences were synthesized de novo and characterized for biological properties relevant to clinical applications. This effort led to the generation of nine functional putative ancestral AAVs and the identification of Anc80, the predicted ancestor of the widely studied AAV serotypes 1, 2, 8, and 9, as a highly potent in vivo gene therapy vector for targeting liver, muscle, and retina.http://www.sciencedirect.com/science/article/pii/S2211124715007597
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Eric Zinn Simon Pacouret Vadim Khaychuk Heikki T. Turunen Livia S. Carvalho Eva Andres-Mateos Samiksha Shah Rajani Shelke Anna C. Maurer Eva Plovie Ru Xiao Luk H. Vandenberghe
spellingShingle	Eric Zinn Simon Pacouret Vadim Khaychuk Heikki T. Turunen Livia S. Carvalho Eva Andres-Mateos Samiksha Shah Rajani Shelke Anna C. Maurer Eva Plovie Ru Xiao Luk H. Vandenberghe In Silico Reconstruction of the Viral Evolutionary Lineage Yields a Potent Gene Therapy Vector Cell Reports
author_facet	Eric Zinn Simon Pacouret Vadim Khaychuk Heikki T. Turunen Livia S. Carvalho Eva Andres-Mateos Samiksha Shah Rajani Shelke Anna C. Maurer Eva Plovie Ru Xiao Luk H. Vandenberghe
author_sort	Eric Zinn
title	In Silico Reconstruction of the Viral Evolutionary Lineage Yields a Potent Gene Therapy Vector
title_short	In Silico Reconstruction of the Viral Evolutionary Lineage Yields a Potent Gene Therapy Vector
title_full	In Silico Reconstruction of the Viral Evolutionary Lineage Yields a Potent Gene Therapy Vector
title_fullStr	In Silico Reconstruction of the Viral Evolutionary Lineage Yields a Potent Gene Therapy Vector
title_full_unstemmed	In Silico Reconstruction of the Viral Evolutionary Lineage Yields a Potent Gene Therapy Vector
title_sort	in silico reconstruction of the viral evolutionary lineage yields a potent gene therapy vector
publisher	Elsevier
series	Cell Reports
issn	2211-1247
publishDate	2015-08-01
description	Adeno-associated virus (AAV) vectors have emerged as a gene-delivery platform with demonstrated safety and efficacy in a handful of clinical trials for monogenic disorders. However, limitations of the current generation vectors often prevent broader application of AAV gene therapy. Efforts to engineer AAV vectors have been hampered by a limited understanding of the structure-function relationship of the complex multimeric icosahedral architecture of the particle. To develop additional reagents pertinent to further our insight into AAVs, we inferred evolutionary intermediates of the viral capsid using ancestral sequence reconstruction. In-silico-derived sequences were synthesized de novo and characterized for biological properties relevant to clinical applications. This effort led to the generation of nine functional putative ancestral AAVs and the identification of Anc80, the predicted ancestor of the widely studied AAV serotypes 1, 2, 8, and 9, as a highly potent in vivo gene therapy vector for targeting liver, muscle, and retina.
url	http://www.sciencedirect.com/science/article/pii/S2211124715007597
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In Silico Reconstruction of the Viral Evolutionary Lineage Yields a Potent Gene Therapy Vector

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