In silico reconstruction of the viral evolutionary lineage yields a potent gene therapy vector

Zinn, Eric; Pacouret, Simon; Khaychuk, Vadim; Turunen, Heikki T.; Carvalho, Livia S.; Andres-Mateos, Eva; Shah, Samiksha; Shelke, Rajani; Maurer, Anna C.; Plovie, Eva; Xiao, Ru; Vandenberghe, Luk H.

doi:10.1016/j.celrep.2015.07.019

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In silico reconstruction of the viral evolutionary lineage yields a potent gene therapy vector

Published Date:

Jul 30 2015

Publisher's site:

http://dx.doi.org/10.1016/j.celrep.2015.07.019 New Site Icon

Source:

Cell Rep. 12(6):1056-1068.

[PDF - 2.53 MB]

Details:

Personal Authors:

Zinn, Eric ; Pacouret, Simon ; Khaychuk, Vadim ; Turunen, Heikki T. ; Carvalho, Livia S. ; ... More ▼

Keywords:

[+]

Pubmed ID:

26235624

Pubmed Central ID:

PMC4536165

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.

Document Type:

Journal Article

Collection(s):

CDC Public Access

Funding:

5DP1EY023177-03/DP/NCCDPHP CDC HHS/United States
DP1 EY023177/EY/NEI NIH HHS/United States
DP1 OD008267/OD/NIH HHS/United States

Supporting Files:

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