Paper Chase

Paper Chase is a research database designed to offer abstracts of research articles published in journals that have a highly rated impact factor as determined by ISI Impact Factor and PageRank. Abstracts are organized by date, with the most recently published papers listed first.

Science (New York, N.Y.)
11 29, 2019 366 (6469) 1139-1143
Vol. 366, Issue 6469, Medline Page 1139-1143

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

Authors: Ogden PJ, Kelsic ED, Sinai S, Church GM
Abstract:
Adeno-associated virus (AAV) capsids can deliver transformative gene therapies, but our understanding of AAV biology remains incomplete. We generated the complete first-order AAV2 capsid fitness landscape, characterizing all single-codon substitutions, insertions, and deletions across multiple functions relevant for in vivo delivery. We discovered a frameshifted gene in the VP1 region that expresses a membrane-associated accessory protein that limits AAV production through competitive exclusion. Mutant biodistribution revealed the importance of both surface-exposed and buried residues, with a few phenotypic profiles characterizing most variants. Finally, we algorithmically designed and experimentally verified a diverse in vivo targeted capsid library with viability far exceeding random mutagenesis approaches. These results demonstrate the power of systematic mutagenesis for deciphering complex genomes and the potential of empirical machine-guided protein engineering.