Comprehensive AAV capsid fitness landscape reveals a viral gene and enables machine-guided design-Reference-Cited by-同舟云学术

Comprehensive AAV capsid fitness landscape reveals a viral gene and enables machine-guided design

Published:2019-11-29 Issue:6469 Volume:366 Page:1139-1143
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Ogden Pierce J.¹²³^ORCID,Kelsic Eric D.¹²⁴^ORCID,Sinai Sam¹²⁴⁵^ORCID,Church George M.¹²³⁴^ORCID

Affiliation:

1. Harvard Medical School, Boston, MA 02115, USA.

2. Wyss Institute for Biomedically Inspired Engineering, Boston, MA 02115, USA.

3. Harvard Graduate Program in Biological and Biomedical Sciences, Boston, MA 02115, USA.

4. Dyno Therapeutics, Inc., Cambridge, MA 02139, USA.

5. Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA.

Abstract

The fitness landscape of AAV Adeno-associated virus (AAV) is an important gene therapy vector. Using tools from synthetic biology, Ogden et al. provide a comprehensive view of how sequence changes in capsid proteins affect AAV properties. After saturation mutagenesis of the AAV2 capsid gene, the resulting library was subjected to multiplexed phenotypic analyses, including virus production, immunity, thermostability, and biodistribution. The mutant distribution to major organs in mice revealed dominant trends affecting in vivo delivery. Moreover, the findings uncovered a viral accessory protein with a role in viral production. Finally, a model built from the capsid fitness landscape enabled machine-guided design of useful variants with much higher efficiency than random mutagenesis. Science , this issue p. 1139

Funder

NIH Office of the Director

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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