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Cell Rep. 2015 Aug 11;12(6):1056-68. doi: 10.1016/j.celrep.2015.07.019. Epub 2015 Jul 30.

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

Author information

1
Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, 20 Staniford Street, Boston, MA 02114, USA; Ocular Genomics Institute, Department of Ophthalmology, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA.
2
Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, 20 Staniford Street, Boston, MA 02114, USA; Ocular Genomics Institute, Department of Ophthalmology, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address: luk_vandenberghe@meei.harvard.edu.

Abstract

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.

PMID:
26235624
PMCID:
PMC4536165
DOI:
10.1016/j.celrep.2015.07.019
[Indexed for MEDLINE]
Free PMC Article

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